Tissue treatment

ABSTRACT

There is provided in accordance with an exemplary embodiment of the a method of selectively treating tissue using non-focused ultrasound energy delivered intrabody comprising: selectively determining a target tissue in a wall of a lumen or cavity; selecting parameters sufficient to provide a desired effect in the target tissue; and applying the parameters to treat the target tissue using non-focused ultrasound to achieve the desired effect.

RELATED APPLICATIONS

This is a PCT application which claims the benefit of priority of U.S. Provisional Patent Applications No. 61/393,947 filed Oct. 18, 2010, and No. 61/453,239 filed Mar. 16, 2011, the contents of which are incorporated herein by reference in their entirety.

The present application is related to co-filed, co-pending and co-assigned patent applications entitled:

“THERAPEUTICS RESERVOIR” (attorney docket no. 52341), which teaches an apparatus and a method for forming a drug reservoir as a possible application of the ultrasound energy application described herein;

“AN ULTRASOUND TRANSCEIVER AND CONTROL OF A THERMAL DAMAGE PROCESS” (attorney docket no. 52342), which teaches an apparatus and method for performing ultrasonic imaging, such as to provide feedback about the effect of treatment on tissues as described herein;

“ULTRASOUND EMISSION ELEMENT” (attorney docket no. 52344), which teaches an apparatus for generating relatively high intensity ultrasound, such as to apply energy to cause the desired effects in tissue as described herein;

“AN ULTRASOUND TRANSCEIVER AND USES THEREOF” (attorney docket no. 52345), which teaches a method for feedback and control of the ultrasonic emission element, such as to use the same ultrasonic element for treatment and imaging, potentially useful when treating and imaging as described herein;

“AN ULTRASOUND TRANSCEIVER AND COOLING THEREOF” (attorney docket no. 52346), which teaches a method for cooling of the ultrasonic emission element, potentially useful when applying energy as described herein;

“SEPARATION DEVICE FOR ULTRASOUND ELEMENT” (attorney docket no. 52348), which teaches a device to prevent the ultrasonic emission element from touching the blood vessel wall, potentially useful for preventing damage to the intima layer when applying energy as described herein;

the disclosures of which are incorporated herein by reference.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to a method of treatment of tissue and, more particularly, but not exclusively, to a method of selectively targeting and treating tissue using unfocused ultrasound energy.

Sverdlik et al, in PCT/IL2008/000234, filed FEB 21, 2008 disclose:

“Described is a method of stabilizing blood vessel wall abnormality. The method includes ultrasonically heating at least a portion of the blood vessel wall having the abnormality; monitoring a parameter related to a property of at least a portion of the heated portion of the blood vessel wall; and stopping the heating when the monitored parameter changes by a predetermined factor or after the monitored parameter changes in a slow enough rate.”

Additional background art includes:

-   EP 1769759 -   U.S. Pat. No. 5,699,804 -   U.S. Pat. No. 7,410,486 -   U.S. Pat. No. 7,621,929 -   U.S. Pat. No. 7,717,948 -   U.S. Pat. No. 7,771,372 -   US patent application 2008228111 -   US patent application 2009216246 -   US patent application 2010091112 -   Xu, D. S., & Pollock, M. (1994). Experimental nerve thermal-injury.     Brain, 117, 375-384. -   Katholi et al. “Renal nerves in the maintenance of hypertension: a     potential therapeutic target” Curr Hypertens Rep. 2010 June;     12(3):196-204. -   Lele, P. P. (1963). Effects of Focused Ultrasonic Radiation on     Peripheral Nerve, With Observations On Local Heating. Experimental     Neurology, 8(1), 47-83. -   Fung L C et al. Effects of temperature on tissue thermal injury and     wound strength after photothermal wound closure. Lasers Surg Med.     1999; 25(4):285-90. -   Worthington, A. E., et al, Ultrasound in Med. & Biol., Vol. 28, No.     10, pp. 1311-1318, 2002. -   Damianou et al, J Acoust Soc Am. 1997 July; 102(1):628-34.

SUMMARY OF THE INVENTION

An aspect of some embodiments of the invention relates to a method of selectively treating a volume of tissue using unfocused ultrasound energy having an acoustic intensity profile of over 1 Watt per square centimeter.

There is provided in accordance with an exemplary embodiment of the invention a method of setting up a treatment system for non-focused ultrasound energy delivered intrabody comprising:

selectively determining a target tissue in a wall of a lumen or cavity;

selecting parameters sufficient to provide a desired therapeutic effect in said target tissue; and

setting up a treatment system using said parameters

In an exemplary embodiment of the invention, the method comprises deciding an amount of desired thermal damage. Optionally, said amount of thermal damage comprises a volume where thermal damage is desired. Optionally or alternatively, said amount of thermal damage comprises the degree of thermal damage.

In an exemplary embodiment of the invention, the method comprises selecting an anatomical location from which to treat said target tissue. Optionally, said anatomical location comprises a renal artery and said target tissue comprises renal artery nerves. Optionally or alternatively, said anatomical location comprises an aorta and said target tissue comprises renal nerves. Optionally or alternatively, said anatomical location comprises a carotid artery and said target tissue comprises nerves.

In an exemplary embodiment of the invention, selecting comprises taking blood cooling into account.

In an exemplary embodiment of the invention, selecting comprises selecting in a manner which avoids significant stenosis.

In an exemplary embodiment of the invention, selecting comprises selecting in a manner which avoids significant damage to non-target tissue.

In an exemplary embodiment of the invention, selecting comprises selecting in a manner which avoids significant shrinkage in target tissue.

In an exemplary embodiment of the invention, said desired effect comprises denaturing at least some of said target tissue. Optionally, the method comprises applying said ultrasound energy so as to not denature at least some part of said target tissue.

In an exemplary embodiment of the invention, said target tissue and said parameters are preselected so that said parameters have said desired effect on said target.

In an exemplary embodiment of the invention, selecting comprises determining according to an attenuation coefficient of tissues.

In an exemplary embodiment of the invention, the method comprises selecting a margin of safety. Optionally, said selecting a margin of safety comprises selecting an allowed amount of thermal damage to tissues surrounding said target tissue. Optionally or alternatively, selecting a margin of safety comprises reducing or preventing contraction of said lumen or said cavity.

In an exemplary embodiment of the invention, selectively determining said target tissue comprises selecting a type of tissue. Optionally, said type of tissue comprises nerve tissue. Optionally or alternatively, said target tissue is selected from tissue located at a tissue layer selected from the group comprising peri-adventitia, adventitia, media, intima.

In an exemplary embodiment of the invention, said target tissue is located less than 10 mm from a renal ostium.

In an exemplary embodiment of the invention, said determining initial parameters comprises determining according to a distance of said target tissue from an intima. Optionally, said target tissue is outside said wall of said lumen or said cavity.

In an exemplary embodiment of the invention, the method comprises selecting a frequency of treatment in the range of 8-25 Mhz.

In an exemplary embodiment of the invention, the method comprises selecting an ultrasound intensity in the range of 1-100 Watt/square centimeter.

In an exemplary embodiment of the invention, said target tissue is a renal nerve, and said parameters are an applied frequency of 10[MHz]-22[MHz], and an intensity of 10-40 [W/cm̂2].

In an exemplary embodiment of the invention, a duration of said treatment is 5-30 seconds.

In an exemplary embodiment of the invention, a length of said lumen or cavity is less than 20 mm.

In an exemplary embodiment of the invention, the method comprises applying said parameters to selectively treat said target tissue using non-focused ultrasound to achieve said desired effect. Optionally, the method comprises obtaining feedback associated with said treatment. Optionally, the method comprises adjusting said parameters according to said feedback and retreating said target tissue.

In an exemplary embodiment of the invention, the method comprises a controlled adjustable treatment according to online measurements including at least one of the following group of measurements: flow measurements, current measurement, voltage measurement, power measurement, acoustic backscatter measurements, temperature measurements, pressure measurements.

In an exemplary embodiment of the invention, treating comprises applying said ultrasound away from said wall but inside a body.

In an exemplary embodiment of the invention, applying so that a desired effect comprises temporary change in tissue functionality is achieved.

In an exemplary embodiment of the invention, said applying said parameters comprises applying said parameters in an open loop manner.

In an exemplary embodiment of the invention, applying comprises applying said ultrasound energy so as to not denature most of the tissue between said target tissue and an edge of said wall.

In an exemplary embodiment of the invention, applying comprises maintaining blood in said lumen at a temperature below 50 degrees Celsius.

In an exemplary embodiment of the invention, applying comprises maintaining blood in said lumen at a temperature below 43 degrees Celsius.

In an exemplary embodiment of the invention, applying comprises heating a nerve while not heating tissue outside of a fat sheath surrounding said nerve.

In an exemplary embodiment of the invention, applying comprises localizing heating by having a gradient of cooling from blood and a gradient of heating from a distance.

In an exemplary embodiment of the invention, applying comprises heating nerves sufficiently to reduce renal norepinephrine levels by at least 50%.

In an exemplary embodiment of the invention, applying comprises heating a part of a nerve to necrosis while not heating another part of said nerve in a same axial location along said nerve to necrosis.

In an exemplary embodiment of the invention, the method comprises adjusting a property of at least one of said target tissue, said wall and blood in said lumen to provide said desired effect. Optionally, said property comprises a rate of heat removal. Optionally or alternatively, said property comprises a flow rate of said blood. Optionally or alternatively, said property comprises a temperature.

In an exemplary embodiment of the invention, applying comprises applying said ultrasound energy so as to treat a patient suffering from hypertension.

In an exemplary embodiment of the invention, applying comprises applying said ultrasound energy so as to prevent signals from propagating through at least one renal nerve.

In an exemplary embodiment of the invention, applying comprises applying said ultrasound energy so as to position said treatment area with an accuracy of better than 0.2 mm along an axis perpendicular to said wall.

There is provided in accordance with an exemplary embodiment of the invention a system configured for carrying out the method as described herein.

There is provided in accordance with an exemplary embodiment of the invention a system for treating a blood vessel wall comprising:

a catheter;

at least one ultrasound emitter mounted on the catheter and adapted for emitting unfocused ultrasound at a frequency of 10-40 Mhz at a target tissue located a distance from an intima of the blood vessel wall with a power setting sufficient to heat said target tissue; and

a controller,

wherein the controller is configured to deliver enough power to heat said target tissue to a selected size and to a desired thermal effect. Optionally, said target tissue comprises nerves, and said desired thermal effect comprises reducing signals through said nerves by at least 50%. Optionally or alternatively, said catheter is configured so that said emitter does not contact said wall. Optionally or alternatively, said controller is configured to selectively treat a volume of tissue distanced from an intima of a blood vessel wall. Optionally or alternatively, said controller is configured for thermal treatment of renal nerves. Optionally or alternatively, said controller is configured for treatment accuracy of better than 0.5 mm positioning of the treatment area, along a dimension perpendicular to said blood vessel. Optionally or alternatively, said controller is configured for treatment specificity which avoids significant vessel stenosis as an aftermath of said treatment. Optionally or alternatively, said controller is configured to selectively heat nerves within a fat sheath thereof. Optionally or alternatively, said controller is configured with a protocol including a plurality of treatment regions and sufficient to reduce hypertension if applied to renal nerves. Optionally or alternatively, said controller is pre-configured with sets of parameters matching different target tissues and target tissue locations. Optionally or alternatively, said controller includes a feedback circuit for real-time control of settings of said system.

There is provided in accordance with an exemplary embodiment of the invention a method of setting up a device to selectively treating tissue using non-focused ultrasound energy delivered intrabody comprising:

setting up said device to be suitable for heating a selected area of tissue at a selected location from an arterial wall.

There is provided in accordance with an exemplary embodiment of the invention a method of treating a blood vessel wall comprising:

adjusting a said blood vessel during intravascular ultrasound treatment, other than by said treatment. Optionally, said adjusting comprises adjusting blood flow through said blood vessel. Optionally or alternatively, said adjusting comprises adjusting a thickness of said blood vessel wall. Optionally or alternatively, said adjusting comprises adjusting a temperature of at least one of said blood and said blood vessel wall.

There is provided in accordance with an exemplary embodiment of the invention a method of setting up a device to selectively treating tissue using non-focused ultrasound energy delivered intrabody comprising:

setting up said device to be suitable for heating nerve tissue while not heating, to a tissue damaging level, tissue outside a fat sheath surrounding said nerve.

There is provided in accordance with an exemplary embodiment of the invention a method of reducing blood pressure comprising:

applying unfocused ultrasonic energy to the renal ostium from within a blood vessel, said energy sufficient to disrupt signals propagating through renal nerves.

There is provided in accordance with an exemplary embodiment of the invention a device for treating blood pressure comprising:

a catheter configured to position an ultrasonic emission element close to a renal ostium, said element configured to emit unfocused ultrasonic energy to nerves. Optionally, close comprises less than 10 mm.

There is provided in accordance with an exemplary embodiment of the invention a method for treating a patient experiencing a clinical disorder, the method comprising:

positioning at least one unfocused ultrasound emitter at an anatomical location proximate to a target tissue;

selectively delivering unfocused ultrasound energy to the target tissue; and

selectively causing thermal damage to at least a portion of the target tissue, to provide a desired treatment. Optionally, the target tissue comprises body lumen, fat, nerves, vasa vasora, lymph, tumor, connective tissue, or plaque. Optionally or alternatively, the anatomical location comprises a blood vessel or artery. Optionally, the anatomical location is the renal artery and the target tissue comprises one or more renal artery nerves. Optionally or alternatively, the at least one unfocused ultrasound emitter is configured not to touch the wall of the blood vessel or artery. Optionally or alternatively, the at least one unfocused ultrasound emitter is positioned as to not substantially block blood flow in the blood vessel or artery. Optionally, the at least one unfocused ultrasound emitter, in operation, is cooled by the blood flow.

In an exemplary embodiment of the invention, the clinical disorder comprises at least one of sleep apnea, obesity, diabetes, end stage renal disease, lesion on a body lumen, contrast nephropathy, heart arrhythmia, congestive heart failure, and hypertension.

In an exemplary embodiment of the invention, the method comprises determining the distance from the blood vessel or artery wall to the target tissue and selecting the frequency of the unfocused ultrasound energy based upon on said distance of the target tissue.

In an exemplary embodiment of the invention, the frequency of the unfocused ultrasound energy is 10-22 Mhz.

In an exemplary embodiment of the invention, the target tissue comprises a treatment region. Optionally, the method comprises determining the treatment region and selecting the intensity of the unfocused ultrasound energy according to the size of the treatment region.

In an exemplary embodiment of the invention, the method comprises delivering the at least one unfocused ultrasound emitter intrabody within the blood vessel or artery by a delivery catheter and configuring the delivery catheter to prevent the at least one unfocused ultrasound emitter from touching the wall of the blood vessel or artery.

In an exemplary embodiment of the invention, the method comprises selecting the target tissue using parameters obtained from an equation based upon empirical data. Optionally, the equation is:

x(f,I) [mm]=(C6+a*Exp(flow*b)−C2*log(C3*I [W/cm̂2]))/(C4*f [MHz]+C5)

Wherein, “I” is excitation intensity [W/cm̂2]; “f” is working excitation frequency [MHz]; “x” is minimal radial distance from the artery wall [mm]; and “flow” is blood flow rate in the artery [ml/mm].

In an exemplary embodiment of the invention, the method comprises receiving feedback indicating the thermal damage to the target tissue. Optionally, the method comprises modifying the parameters in response to said feedback.

In an exemplary embodiment of the invention, the method comprises selectively delivering the unfocused ultrasound energy in a manner such that there is no significant damage to non-target tissue.

In an exemplary embodiment of the invention, the method comprises selectively delivering the unfocused ultrasound energy in a manner such that there is no significant stenosis.

In an exemplary embodiment of the invention, the method comprises delivering unfocused ultrasound energy to at least one treatment region, each treatment region being at a separate circumferential location. Optionally, the duration that unfocused ultrasound energy is delivered to the target tissue is 5-30 seconds per treatment region. Optionally or alternatively, the treatment comprises between 1 and 8 treatment regions.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

Implementation of the method and/or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.

For example, hardware for performing selected tasks according to embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to exemplary embodiments of method and/or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data. Optionally, a network connection is provided as well. A display and/or a user input device such as a keyboard or mouse are optionally provided as well.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1A is a flowchart of a treatment method, in accordance with an exemplary embodiment of the invention;

FIG. 1B is a flowchart of a more detailed treatment method of FIG. 1A, in accordance with an exemplary embodiment of the invention;

FIG. 2 is an illustration of an embodiment of the treatment system for selectively treating tissues, in accordance with an exemplary embodiment of the invention;

FIG. 3 is an illustration of the human body showing exemplary treatment locations, useful in practicing some embodiments of the invention;

FIG. 4 is an illustration of the renal artery, showing exemplary treatment locations, in accordance with an exemplary embodiment of the invention;

FIG. 5 is an illustration of ultrasound energy treating tissues, in accordance with an exemplary embodiment of the invention;

FIG. 6A is a cross section of an arterial wall, illustrating selective tissue treatment, in accordance with an exemplary embodiment of the invention;

FIG. 6B is a cross sectional view, FIG. 6C is a side view and FIG. 6D is a top view illustrating a controllable volume of thermal effect to tissue, in accordance with an exemplary embodiment of the invention;

FIG. 7A is an exemplary graph illustrating a temperature profile, useful in practicing some embodiments of the invention;

FIG. 7B is an exemplary graph illustrating relative tissue attenuation, useful in practicing some embodiments of the invention;

FIG. 7C is an exemplary graph illustrating some associations between heat removal rates and treatment, useful in practicing some embodiments of the invention;

FIGS. 7D-7E illustrate the adjustment of one or more tissue properties, in accordance with some embodiments of the invention;

FIG. 8 is an exemplary graph illustrating some associations between frequency and treatment, useful in practicing some embodiments of the invention;

FIG. 9 is an exemplary graph illustrating some associations between ultrasound intensity profile and treatment, useful in practicing some embodiments of the invention;

FIG. 10 is a flow chart of monitoring during treatment, in accordance with an exemplary embodiment of the invention;

FIG. 11 is a flow chart of feedback during treatment, in accordance with an exemplary embodiment of the invention;

FIG. 12A is a table summarizing experimental results obtained using some embodiments of the invention;

FIG. 12B is a table summarizing experimental results at 10 Mhz, obtained using some embodiments of the invention;

FIG. 12C is a table summarizing experimental results at 20 Mhz, obtained using some embodiments of the invention;

FIG. 12D illustrates graphs summarizing the values in FIGS. 12B-12C, useful in practicing some embodiments of the invention;

FIG. 12E is an image illustrating the variables described in FIGS. 12B-12D, useful in practicing some embodiments of the invention;

FIGS. 13A-B are graphs of associations between thermal damage results and ultrasound parameters according to the results of FIG. 12A, useful in practicing using some embodiments of the invention;

FIGS. 13C-H are exemplary graphs of thermal damage results and ultrasound parameters according to the results as shown in FIGS. 12B-12D, useful in practicing some embodiments of the invention;

FIGS. 14A-C are images of experimental results in the aorta obtained using some embodiments of the invention;

FIGS. 15A-D are images of experimental results in the aorta obtained using some embodiments of the invention;

FIGS. 16A-C are images of experimental results in the carotid artery obtained using some embodiments of the invention;

FIGS. 17A-B are images of experimental results in the carotid artery obtained using some embodiments of the invention;

FIGS. 18A-G are images of experimental results in the renal artery obtained using some embodiments of the invention;

FIGS. 19A-C are images of experimental results in the renal artery obtained using some embodiments of the invention; and

FIGS. 20A-J are images of experimental results in the renal artery obtained using some embodiments of the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to a method of treatment of tissue and, more particularly, but not exclusively, to a method of selectively targeting and treating tissue using unfocused ultrasound energy. In an exemplary embodiment of the invention, the tissue is in a mammal, for example, a pig or a human.

An aspect of some embodiments of the invention relates to a method of selectively treating tissue using ultrasound energy delivered intrabody. Optionally, the ultrasound energy is non-focused.

In an exemplary embodiment of the invention, tissues can be targeted spatially, for example, a volume of tissue located in a wall of a blood vessel. Optionally, the tissue to be targeted is defined spatially, for example, using x, y, z coordinates.

In an exemplary embodiment of the invention, target tissues are treated with ultrasound energy, for example, heated using ultrasound energy. Optionally, tissues are thermally damaged, non-limiting examples of damage include; burning, coagulation, denaturation, ablation, necrosis, disruption (e.g., of signal propagation in nerves), degeneration, destruction. Optionally or additionally, tissues are heated sufficiently without causing immediate damage and/or shrinkage.

In an exemplary embodiment of the invention, target tissues are heated to a selected temperature. For example, about 43, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95 degrees Celsius, or other smaller, intermediate or larger temperatures are used, or subranges thereof.

In an exemplary embodiment of the invention, the time to reach the peak temperature is selected. For example, about 0.1 seconds, about 1 second, about 3 seconds, about 5 seconds, about 10 seconds, about 15 seconds, about 30 seconds, or other smaller, intermediate or larger values are used.

In an exemplary embodiment of the invention, the acoustic intensity profile is high intensity, for example, about 11-20, or 21-30 or 31-40, or 41-50 or 51-60 or 61-70 or >=71 Watt/square centimeter, or other smaller, intermediate or larger values are used.

In an exemplary embodiment of the invention, the initial thermal effect is selected to start away from the intima of the artery, for example, about 0.2 mm away from the intima, or 0.3 mm, 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 7 mm, away, or other smaller, intermediate or larger distances are selected.

In an exemplary embodiment of the invention, the location, the volume and/or the extent of the thermal effect is selected.

In an exemplary embodiment of the invention, the treatment is selected to treat only a portion of the target tissue, for example, half of the target tissue. Alternatively, the treatment is selected to treat the entire target tissue.

In an exemplary embodiment of the invention, the treatment is selected according to safety considerations. Optionally, a safety consideration is treating with a margin of safety around the target tissue, for example, the treatment is selected to treat the target tissue without treating surrounding tissue. Alternatively, the treatment is selected to treat at least some tissue surrounding the target tissue. Alternatively or additionally, a safety consideration is side effects of treatment, for example, treatment is selected to reduce and/or prevent contraction (e.g., stenosis) of the artery, for example, due to scarring of tissue in the arterial wall.

In an exemplary embodiment of the invention, the treated is selected for a type of tissue. Optionally, the treatment is selected towards nerves in the adventia or peri-adventitia. Optionally or additionally, the treated is selected towards nerves are in the renal artery wall. Alternatively, the treatment is selected towards renal nerves in the aorta. Alternatively, the treatment is selected towards nerves in the carotid artery wall.

In an exemplary embodiment of the invention, the treatment is selected by taking into account the cooling capacity of the vessel wall, such as a blood flow in the artery.

In an exemplary embodiment of the invention, the frequency of vibration of the acoustic element of the transducer is selected according to the depth of the target tissue.

In an exemplary embodiment of the invention, the ultrasonic intensity profile is selected according to the size of the treatment region. Optionally, a relatively low ultrasonic intensity profile treats a relatively small area in the peri-adventitia. Optionally, a relatively higher ultrasonic intensity profile is selected to increase the treatment region from the peri-adventitia towards the intima, for example until the adventia, until the media, or to increase the size of the treatment region in the peri-adventia.

In an exemplary embodiment of the invention, one or more tissue properties are adjusted, for example, increased and/or decreased. Non-limiting examples of tissues include; target tissue, surrounding tissue, blood flowing in vessel. Optionally, tissue properties are adjusted in accordance with the selected thermal effect, for example, to relatively increase the size of the thermally affected area. Optionally or additionally, tissue properties are adjusted in accordance with the selected safety parameters, for example, to relatively increase the margin of safety. Non-limiting examples of tissues properties that are adjusted include; the temperature of the tissue, the heat removal rate from the tissue, the acoustic energy absorption of the tissue.

In an exemplary embodiment of the invention, feedback associated with the treatment is obtained. Optionally, the desired result is used as a target, such as in an open-loop manner. For example, initial parameters are set and the tissue is treated to achieve the result. Alternatively or additionally, the desired result is used as feedback of the treatment, such as in a close-loop manner. For example, treatment is applied, imaging of the treatment region is performed to check if the desired result has been met and treatment is reapplied, optionally with adjustments to the treatment.

In an exemplary embodiment of the invention, the treatment region is defined by a circumferential extent and by a distance extent and also by a starting distance (e.g., from an intima). In an exemplary embodiment of the invention, the distance extent and/or starting distance are controlled with an accuracy of, for example, better than 2 mm, 1 mm, 0.5 mm, or 0.2 mm. Optionally or alternatively, the circumferential extent of treatment is controlled with an accuracy of better than 30 degrees, 10 degrees, or 5 degrees, which can be, for example, 3 mm, 2 mm, 1 mm, 0.5 mm or better or intermediate accuracy.

In an exemplary embodiment of the invention, the amount, pattern and/or extent of the treated region is selected according to a desired effect and/or a probability of affecting sufficient tissue to be treated (e.g., nerves). Optionally, the amount of treatment is curtailed, for example, to reduce side effects, such as constriction of the lumen caused by too much damage in the lumen wall.

In an exemplary embodiment of the invention, for a section of treated lumen of, for example, 1-5 cm in length (e.g., axial distance between outermost treatment locations), the percentage of axial locations treated is, for example, 10%, 30%, 50%, 80% or smaller or intermediate or greater percentages.

In an exemplary embodiment of the invention, when considering the surface area of the intima of such a treated section, and mapping treated regions by “collapsing” them towards the intima, the percentage of area treated can be, for example, 5%, 15%, 30%, 60%, 80% or smaller or intermediate or larger percentages.

In an exemplary embodiment of the invention, when considering the circumference of the intima of such a treated section at an axial location where treatment is applied, and mapping treated regions by “collapsing” them towards the intima, the percentage of circumference treated can be, for example, 5%, 15%, 30%, 60%, 80% or smaller or intermediate or larger percentages, for example, for between 1 and 8 axial treatment locations.

A particular feature of some embodiments of the invention is that an extent of treatment in a dimension perpendicular to the lumen wall is affected both by cooling of the lumen wall, e.g., by natural blood flow and by dissipation of energy as the energy penetrates into the tissue. In an exemplary embodiment of the invention, the frequency and/or other properties of the energy affect the absorption per unit distance, which results in reduced energy deposition as distance increases. Optionally or alternatively, cooling effects of nearby tissue reduce energy deposition. Optionally or alternatively, divergence of the beam reduces energy deposition. Optionally or alternatively, tissue properties, for example, insulation of a sheath surrounding nerves, serves to increase the effect of energy deposition at some tissues. Optionally or alternatively, tissue characteristics affect energy deposition thereat.

A particular feature of some embodiments of the invention is the use of an unfocused energy field, which, in some embodiments, can preserve a uniform definition of its edges for a considerable distance, thereby providing definition of circumferential edges of a treated area.

A particular feature of some embodiments of the invention relates to the ability to reduce mechanical positioning requirements while maintaining and/or increasing accuracy of spatial selectivity of treatment.

With respect to a direction perpendicular to the vessel wall, in a focused system, position control is provided by accurate focusing and control of catheter position (e.g., to be in contact with a wall). In an exemplary embodiment of the invention, however, position control in that direction is provided by a tradeoff between cooling by blood flow and energy application. This is not dependent on the catheter position in a blood flow, as there is relatively little loss in the blood, in some embodiments. This means that variations of several millimeters in catheter distance form the wall need not have a significant effect on spatial treatment location. Moreover, not having contact with the vessel wall can ensure, in some embodiments, sufficient cooling to prevent damage at any part of the intima.

Use of non-focused beams can also help in the circumferential accuracy requirements. In one example, it allows the treated “spot” to be quite large, which means there need not be any scanning of a focal point of a focused beam, which scanning may be complex and/or inaccurate. Optionally, the circumferential profile of the beam is selected so that it provides a gradual cut-off in degree of damage, for example, along a border of, for example, 1-2 mm in width. Alternatively, a sharp cut-off is provided, for example, by suitable selection of emitter design to have a sharp cut-off in intensity profile.

In an exemplary embodiment of the invention, provision of high power allows the treatment time to be short enough so that, for example, treatment can be applied while blood velocity is constant (e.g., during cardiac disatole) and/or while the vessel wall is not moving (e.g., relative to catheter, which is optionally determined using a distance sensor and/or estimated using a pulse sensor and/or ECG sensor).

In an exemplary embodiment of the invention, cooling of an ultrasonic emitter by blood flow allows higher power to be used.

Overview of Treatment

FIG. 1A is a flow chart of a method of selectively treating tissues using ultrasound energy, in accordance with an exemplary embodiment of the invention. Optionally, the ultrasound energy is applied at a selected frequency. Optionally or additionally, the ultrasound energy is applied at a selected intensity profile (e.g., watts per square centimeters, time of treatment). The method described in the flowchart is non-limiting. For example, some steps are optional. Furthermore, there can be other methods and/or other apparatus used to obtain the results.

At 102, a target tissue is optionally determined, for example, to treat a clinical disorder by thermally damaging (e.g., ablating) the target tissue, in accordance with an exemplary embodiment of the invention.

In an exemplary embodiment of the invention, one or more factors related to the thermal effect are optionally determined (e.g. manually by a physician, automatically by software), for example, the anatomical location (e.g., the blood vessel where the catheter will be inserted) of the lesion, the type of tissue to ablate (e.g. nerve), an extent of the thermal effect (e.g., the entire tissue, part of the tissue), and/or safety considerations.

At 104, one or more parameters to result in the desired thermal effect of the target tissue are optionally determined, in accordance with an exemplary embodiment of the invention.

Optionally, feedback is obtained about the treatment effect, for example, imaging of the target tissues. Alternatively, feedback is not required, as the initial settings are sufficient to achieve the desired treatment effect.

In an exemplary embodiment of the invention, localization of the treatment effect is optionally provided by one or more factors including, the blood cooling the vessel wall, the ultrasonic beam amplitude attenuation, the ultrasonic beam dispersion, and/or tissue types.

At 106, the target tissue as determined in 110 is treated using parameter settings as in 104, in accordance with an exemplary embodiment of the invention. Optionally, ultrasound energy is delivered by a transducer on a catheter inserted into the body. Optionally, the treatment is monitored.

Optionally, at 108, treatment is repeated, for example, immediately and/or at a later point in time. Optionally, treatment is adjusted in response to feedback.

In an exemplary embodiment of the invention, feedback optionally is related to the parameters used for transmission of ultrasonic energy, for example, associated with the treatment intensity profile. Optionally, feedback is related to the environment, for example, the rate of blood flow. Alternatively or additionally, feedback is related to the impedance of the acoustic element, such as to estimate changes in efficiency that can affect the transmitted acoustic intensity profile.

In an exemplary embodiment of the invention, feedback is optionally functionally related to the effects of the ultrasonic energy on tissues. Optionally, feedback in the form of imaging is used to detect the effect of treatment on tissues. Alternatively or additionally, feedback in the form of clinical measurements (e.g., blood pressure changes) are used to detect the effect.

In some embodiments, imaging is optionally used to evaluate the treatment (e.g., thermal damage to target tissue). Alternatively or additionally, the treatment is evaluated using other methods, such as clinical measurements, sometimes over the long term.

Control System

FIG. 2 illustrates an exemplary ultrasound treatment system 1600 for selectively treating tissues, in accordance with an exemplary embodiment of the invention. System 1600 provides for the control of the ultrasound treatment and/or monitoring of the treatment using catheter 1222. A transducer 300 comprising an acoustic element 102 to produce ultrasound energy is optionally located on a distal end of catheter 1222.

In an exemplary embodiment of the invention, an operator (e.g., physician performing the procedure) programs a controller 1602 (e.g., computer) for treatment using a user interface 1604 (e.g., keyboard, mouse, monitor). Optionally, treatment is monitored, for example, by viewing feedback parameters on interface 1604.

In an exemplary embodiment of the invention, a power port 1606 provides electrical power to electrodes across element 102, causing element 102 to vibrate at the set frequency, outputting a set ultrasound intensity profile.

In an exemplary embodiment of the invention, one or more functions and/or parameters and/or settings are programmed and/or set into controller 1602 (e.g., automatically determined by software such as according to a treatment plan). Optionally or additionally, one or more functions and/or parameters are selectable (e.g., manually set by a user, automatically selected by software).

One or more non-limiting examples of settable parameters include:

-   -   Impedance of element 102.     -   Acoustic feedback is feedback obtained by analyzing echoes of a         diagnostic ultrasound signal returning from tissues, for         example, as will be described in more detail with reference to         FIG. 11.     -   Estimated or measured flow rate of blood across the surface of         the acoustic element is important for controlling the         temperature of the element to prevent overheating. In some         embodiments, the flow rate of the blood is adjusted relatively         higher or relatively lower, such as to control the temperature.     -   Estimated or measured flow rate of blood across the wall of the         treatment target (e.g., blood vessel) is important for         estimating the cooling capacity of the blood on the tissues of         the wall being heated by ultrasound.     -   Efficiency is the estimated efficiency of converting electrical         energy into ultrasound energy by the acoustic element.     -   Temperature control system cools and/or heats the element and/or         tissues (e.g., blood vessel wall) to the desired temperature.         Optionally, the temperature control system is used in         combination with the blood flow. In some embodiments, the blood         and/or tissue is pre-heated, for example, to obtain a relatively         larger thermal effect.     -   Impulse excitation is the application of an impulse function         (e.g., delta function) to the element, causing the element to         vibrate with a decreasing amplitude. Impulse excitation is used         to estimate a reduction in efficiency, useful as feedback, for         example, to determine one or more of, thrombus formation on the         element, the element coming in contact with the vessel wall,         mechanical damage to the element.     -   Navigation system controls the movement and/or positioning         and/or orientation of catheter 1222 and/or the transducer.     -   Pressure is the pressure caused by sound (e.g., acoustic         intensity) during treatment and/or imaging.     -   Electric power is the applied power to the transducer.     -   Reflected electric power from the transducer back to the         controller.     -   Voltage is the measured and/or applied voltage on the         transducer.     -   Current is the measured and/or applied current in the         transducer.

One or more non-limiting examples of selectable parameters include:

-   -   Frequency of the ultrasound energy produced by vibration of the         acoustic element.     -   Waveform applied to the acoustic element, for example, a         sinusoidal wave form.     -   Intensity is the produced ultrasound power divided by the         surface area of the acoustic element.     -   Pulse duration is the length of a pulse of acoustic energy         measured in time.     -   Duty cycle is the percentage of time in a single pulse that         ultrasound energy is transmitted.     -   Temperature threshold is the approximate temperature of the         element and/or the liquid (e.g., blood, saline) that should not         be exceeded.     -   Treatment pattern is the spatial and/or temporal combination of         one or more of the above variables, for example, a single pulse,         a sequence of pulses, a train of pulses.     -   Focusing is the setting of non-focused vs. focused ultrasound         energy.

The table below sets out some examples of the selectable parameters, and provides their theoretical limits, an exemplary treatment range, and an exemplary treatment sub range (e.g., most commonly used settings). It is important to note that some selectable parameters can only be selected from a pre-determined set, for example, in some embodiments, catheters are designed to operate at a specific frequency, in which case the user selects the frequency according to the catheter available.

Exemplary Exemplary Theoretical Treatment Treatment Parameter range range sub range Frequency (MHz): Treatment 1-60 8-30 10-22 Imaging 1-60 10-60  10-25 Intensity (Watts/sq cm)  1-200 10-100 10-60 Duty cycle (%) 0.1-100  10-100  50-100 Pulse duration (seconds) 0.01-1000  0.1-4   0.1-2  Duration of treatment  0.1-1000  2-120  3-60 (Seconds) per location Efficiency (%)  1-70%  20-70%  35-70% Temperature (Celsius) 10-100 15-80  25-80 Some Examples of Expected Effects Associated with Variables

The following are some non-limiting examples illustrating some parameters under control, and their association with some expected treatment effects, in accordance with an exemplary embodiment of the invention:

-   -   Impedance: a decrease of more than 10% suggests a decrease in         efficiency of the acoustic element. The element will heat up         more (e.g., requiring more cooling), and/or the acoustic         intensity will decrease (e.g., requiring a higher intensity). In         some embodiments, the impulse excitation is used to estimate the         change in efficiency.     -   Acoustic feedback: imaging of the treatment region for the         desired thermal effects can be used to decide if to continue         treatment, stop treatment or change treatment (e.g., increase or         decrease acoustic intensity profile, change positions of         catheter).     -   Estimated flow rate of blood across acoustic element: a change         in blood flow can cause the element to overheat, potentially         damaging the element.     -   Estimated flow rate of blood across wall of blood vessel: a         decrease in flow rate reduces the cooling of tissues,         potentially resulting in a larger thermal effect for the given         acoustic intensity. An increase in flow increases the cooling of         the tissues, potentially resulting in a smaller thermal effect.         Alternatively, the location of the thermal effect will be         shifted. In some embodiments, the flow rate is controlled to         within a predetermined range (e.g., as will be described below).         Alternatively or additionally, the acoustic intensity profile is         adjusted. Alternatively or additionally, the cooling system is         used to maintain the temperature of the element and/or wall         within the range.     -   Navigation system: imaging feedback can be used to detect if the         thermal effect is at the desired location (e.g., to the target         tissue). Adjustments in position can be made accordingly.     -   Frequency: a relatively lower frequency of ultrasonic energy is         able to penetrate relatively deeper into tissue. In some         embodiments, relatively lower frequencies are used to achieve         thermal effects relatively further away from the blood vessel         wall.     -   Intensity: a relatively higher intensity of ultrasonic energy is         able to penetrate relatively deeper into tissue and/or achieves         a relatively higher heating of tissues quicker. In some         embodiments, relatively higher intensities are used to achieve         relatively larger thermal effects. Alternatively or         additionally, thermal effects are further away from the vessel         wall.     -   Pulse duration: a relatively longer pulse will deliver a         relatively larger amount of ultrasonic energy to tissues,         achieving a relatively larger thermal effect.     -   Duty cycle: a relatively higher duty cycle will deliver a         relatively higher amount of ultrasonic energy to tissues,         achieving a relatively larger thermal effect. In some         embodiments, a relatively short duty cycle acts as a train of         short pulses separated by delays, the effect of which is         described below with reference to ‘treatment pattern’.     -   Treatment Pattern: can be applied to achieve various treatment         objectives, for example, a pulse of acoustic energy can be         applied, followed by a delay period to allow cooling (e.g., by         spreading of heat) before applying another pulse of energy. In         another example, tissue can be targeted for treatment at one         location, followed by a rotation (e.g., 10 degrees), followed by         treatment at the second location, followed by a rotation to the         first location.     -   Focusing: non-focused application of energy does not require         precise anatomical positioning of the distance from the         transducer to the target tissue throughout treatment, and         achieves a relatively larger treatment volume using a relatively         lower acoustic intensity. Focused application of energy requires         precise positioning of the focal point to the target tissue         throughout treatment, and achieves a relatively smaller         treatment volume using a relatively higher intensity (e.g.,         total intensity at focal point).

Exemplary Method of Treatment

FIG. 1B is a detailed method of treatment of FIG. 1A, in accordance with an exemplary embodiment of the invention. It should be noted that the method described in the flowchart is non-limiting. For example, some steps are optional. Furthermore, there can be other methods and/or other apparatus used to obtain the results.

Optionally, at 152, a decision to treat is made, for example, as will be described in the section “DECIDING TO TREAT”.

Optionally, at 154, the anatomical location to treat is selected, for example, as will be described in the section “SELECTING ANATOMICAL LOCATION OF TREATMENT”.

Optionally, at 156, a decision is made with regards to the amount of thermal damage to cause, for example, as will be described in the section, “DECIDE AMOUNT OF THEMAL EFFECT”.

Optionally, at 158, a decision is made with regards to tradeoffs related to safety considerations, for example, increasing the margin of safety will result in less damage to surrounding tissue, but may not result in full treatment of the target tissue, for example, as will be described in the section “DECIDE SAFETY CONSIDERATIONS”.

Optionally, at 160, the rate of blood flow in the artery is estimated, for example, as will be described in the section “ESTIMATE BLOOD FLOW”.

Optionally, at 174, one or more tissue properties of the target tissue and/or surrounding tissue are adjusted, such as temperature and/or heat removal rate, for example, as will be described in the section “ADJUSTING TISSUE PROPERTIES”. In some embodiments, the tissue properties are adjusted according to one or more parameters, such as the amount of thermal effect and/or safety considerations.

Optionally, at 162, the frequency of the ultrasound energy to apply is selected, such as by choosing a catheter designed to operate at that frequency, for example, as will be described in the section “CHOOSE CATHETER (FREQUENCY) ACCORDING TO TREATMENT”. In some embodiments, the user is limited in the selection of the frequency according to the available frequency. At 164, the ultrasonic intensity profile is selected according to the treatment (e.g. watts per square centimeter, time of treatment, profile over time) for example, as will be described in the section “CHOOSE ULTRASONIC INTENSITY PROFILE ACCORDING TO TREATMENT”.

Optionally, at 166, the catheter (e.g., as selected in 162) is inserted into the body of the patient and threaded to the treatment site (e.g., as selected in 154), for example, as will be described in the section “INSERT CATHETER”.

At 168, the patient is treated, for example, as will be described in the section “TREAT”.

Optionally, at 170, feedback is obtained, for example, as will be described in the section “FEEDBACK”.

Optionally, at 172, adjustments are made, for example, to one or more parameters, and treatment continues as in 168, for example, as will be described in the section “ADJUST”.

Deciding to Treat

In an exemplary embodiment of the invention, a decision to treat by thermally damaging target tissue is made, for example, by a physician according to clinical indications.

Non-limiting examples of clinical applications are listed in the table below. The applications listed in the table are referenced (e.g., according to numbers) to FIG. 3, which is an illustration of the human body showing the major arteries as reference points, useful in practicing some embodiments of the invention.

Exemplary Clinical Applications

# Application Name Anatomy Target 402 Renal sympathetic Renal artery Renal sympathetic nerve modulation nerves 404 Carotid sympathetic Carotid artery Carotid sympathetic nerve modulation nerves 406 Vagus sympathetic Aorta Vagus sympathetic nerve modulation nerve 408 Peripheral sympathetic Peripheral Peripheral sympathetic nerve modulation blood vessels nerves 410 Pain nerve modulation Spinal cord Pain nerves cannel 412 Restenosis decrease All relevant Artery media and arteries adventitia 414 Vulnerable plaque All relevant Artery media and stabilization arteries adventitia 416 Atherosclerosis All relevant Artery media and passivation arteries adventitia 418 Plaque volume decrease All relevant Artery media and arteries adventitia 420 Plaque thrombosis All relevant Artery media and decrease arteries adventitia 422 Tetanic limb muscle Limb arteries Peripheral motor tonus decrease or veins nerves 424 Atrial fibrillation Right atria Pulmonary vain prevention insertion 426 Cardiac arrhythmia Coronary Cardiac tissue prevention arteries pathology 428 Liver tumor necrosis Inferior vena Tumor cava 430 None-malignant Urethra Sick prostate tissue prostate treatment 432 Malignant prostate Urethra Sick prostate tissue treatment 434 Artery aneurysms All relevant Aneurysm wall stabilization arteries 436 Aortic aneurysms Aorta Aneurysm wall stabilization 438 Berry aneurysms Brain arteries Aneurysm wall sealing 440 Erectile dysfunction Internal Iliac Artery media and treatment adventitia

A non-limiting method of stabilizing a plaque and/or aneurysm using ultrasound energy is described for example, in Sverdlik et al, in PCT/IL2008/000234, incorporated herein by reference in its entirety.

In an exemplary embodiment of the invention, nerve tissue is selectable for treatment by ultrasonic energy, for example, as will be described below with reference to FIG. 7B.

Some exemplary medical conditions and their proposed treatment by treating nerves (examples not limited to the nerves described, treating other nerves may achieve a similar clinical outcome) in accordance with an exemplary embodiment of the invention include:

-   -   Frozen shoulder—suprascapular nerve.     -   Zygapophysial joint pain—cervical medial branch nerves.     -   Chronic Pelvic Pain (in women)—uterosacral nerve.     -   Glabellar Frowning—facial nerve.     -   Phantom Pain—lumbar dorsal root ganglia.     -   Trigeminal Neuralgia—branches of the trigeminal nerve.     -   Cluster Headache—trigeminal and/or sphenopalatine ganglions.     -   Complex Regional Pain Syndrome—stellate ganglion.

In some embodiments, electrical signals through nerves are reduced by treatment, for example, by damaging some neurons in the nerve bundle. Alternatively or additionally, electrical signals through nerves are prevented from passing through, for example, by damaging the entire nerve bundle.

In some embodiments, malignant tissues (e.g., in the liver) and/or hypertrophic tissues (e.g., in the prostate) are damaged.

In some embodiments, the parameters to treat the tissues are obtained from a mathematical model, for example, as described in the section “EXEMPLARY DEVELOPMENT OF AN EQUATION” parts A and/or B.

Some non-limiting examples of how to achieve various desired effects using some embodiments of the invention are described. The description refers to obtaining the described effect. However, it should be noted that some effects overlap, and so some embodiments achieve one or more effects. In some embodiments, only the desired effect is achieved without other effects.

-   -   Coagulation—In some embodiments, heating tissue including blood         to the range of 42-55 or 42-50 or other smaller, intermediate or         larger values, results in blood coagulation without damage to         surrounding tissues.     -   Denaturation—In some embodiments, heating tissue above 50, above         55, above 60 or other smaller, intermediate or larger values         results in denaturation of collagen.     -   Apoptosis—In some embodiments, tissues are heated to over 85,         over 95 degrees Celsius, or other smaller, intermediate or         larger values to cause apoptosis, for example, as taught by Fung         et al. Tissues affected are located about 0-0.5 mm away from the         area of the applied energy.     -   Temporary/permanent disruption of nerve signals—In some         embodiments, the length of nerve that is disrupted (e.g.,         burned) is selected to result in temporary or permanent         disruption of nerve signals. For example, a relatively short         disruption length can allow nerves to regenerate and reconnect,         for example, about 0.1 mm, about 0.5 mm, about 1 mm, about 2 mm,         about 5 mm, or other smaller, intermediate or larger values are         used. Optionally, relatively long disruption lengths prevent         nerves from regenerating and reconnecting, for example, about 10         mm, about 15 mm, about 20 mm, about 30 mm, or other smaller,         intermediate or larger values are used.     -   Destruction—In some embodiments of the invention, tissues are         heated to over 100 degrees Celsius to result in tissue         destruction. A temperature of over 100 degrees Celsius results         in vaporization of water, which can cause cells to burst.     -   Burning—In some embodiments, tissues are heated for relatively         long periods of time to result in burning of the tissue, for         example, over 10, 20, 30, 50, 100 seconds, or other smaller,         intermediate or larger time periods. Alternatively or         additionally, relatively high intensities are applied to result         in the burn.     -   Degeneration—In some embodiments, tissues are heated to cause         degeneration of the tissue, such as to about 47 degrees Celsius,         for example, as taught by Xu & Pollock (see below).

Selecting Anatomical Location of Treatment

In an exemplary embodiment of the invention, the anatomical location for treatment (e.g., thermal effect) is selected. Optionally, a factor in the selection is the ability to apply ultrasound energy to the target tissue. One or more non-limiting examples of target tissues include, fat, nerves, vasa vasora, lymph, tumor, connective tissue, plaque (e.g., atherosclerotic).

In an exemplary embodiment of the invention, ultrasonic energy is applied invasively, for example, using a catheter and/or an endoscope. Alternatively, ultrasonic energy is applied non-invasively. Non-limiting examples from which thermal effects can be applied include one or more of, a fluid filled lumen (e.g., blood vessel), a non-fluid filled lumen (e.g., ureter), a fluid filled cavity (e.g., spinal canal), a non-fluid filled cavity (e.g., stomach), from outside the body (e.g., ultrasonic transducer is placed in a liquid such as water, and energy is delivered across the skin).

In an exemplary embodiment of the invention, a decision on the location of treatment is made from one or more different possible anatomical locations. Optionally, a factor in the selection is the location inside the lumen from which ultrasonic energy is applied, for example some locations are more easily accessed by using a catheter than others. Alternatively or additionally, a factor in the selection is the rate of blood flow in the blood vessel where the catheter will be positioned (e.g., some areas have more uniform flow), potentially important for cooling, for example, as will be described in the section “Estimate blood flow”. In some cases, similar clinical effects will be achieved by thermal effects (e.g., damage) of at least one of the different locations.

For example, a treatment of resistant essential hypertension is renal denervation. Reference is made to FIG. 4, which is an illustration of the anatomy of renal nerves 350 in relation to a right renal artery 352. Right renal artery 352 supplies blood to a right kidney 354 from an aorta 356. Commonly, renal nerves 350 arise from T10-L2 spinal roots, travel along aorta 356 and along renal artery 352 to innervate kidney 354. In some anatomies, renal nerves 350 primarily lie within the adventia of the renal artery 352 and/or aorta 356.

Non-limiting examples of conditions likely to respond to renal denervation:

-   -   Resistant essential hypertension.     -   Essential hypertension intolerant to medications.     -   Nondipping essential hypertension.     -   Resistant renovascular hypertension.     -   Hypertension with chronic renal disease (unilateral or         bilateral).     -   Hypertension with obstructive sleep apnea intolerant to         continuous positive airway pressure.     -   Congestive heart failure (with reduced or preserved left         ventricular systolic function) with cardiorenal syndrome.     -   Hypertension in end-stage kidney disease on dialysis with native         kidneys.     -   Hypertension in renal transplant patients with remaining native         kidneys.         Non-limiting examples of potential long-term benefits of renal         denervation:     -   Attenuation of arterial pressure.     -   Stabilization of renal function with attenuation of the rate of         decline of estimated glomerular filtration rate and reduction of         proteinuria in hypertensive patients.     -   Restoration of nocturnal dipping.     -   Regression of left ventricular hypertrophy.     -   Decreased insulin resistance.     -   Slower progression of vascular disease.     -   Decreased incidence of congestive heart failure with reduced         ventricular hypertrophy, reduced salt and water retention, and         improved exercise tolerance.     -   Decreased risk of stroke.     -   Decreased risk of atrial and ventricular arrhythmias.     -   Decreased risk of sudden cardiac death.

Further details about renal denervation can be found in an article by Katholi et al. “Renal nerves in the maintenance of hypertension: a potential therapeutic target” Curr Hypertens Rep. 2010 June; 12(3):196-204, incorporated herein by reference in its entirety.

There are one or more exemplary locations for performing the renal denervation procedure, useful in practicing some embodiments of the invention. For example, the procedure can be performed at a renal artery location 358 (e.g., from inside renal artery 352), at an ostium location 360 (e.g., the branch of renal artery 352 off aorta 356) and/or at an aorta location 362 (e.g., from inside aorta 356).

Non-limiting examples of factors affecting the location (e.g., 358, 360, 362) of treatment include simplicity of access, simplicity of the treatment procedure. For example, at location 358 multiple treatment areas may be required to ablate enough renal nerves 350 to achieve a desired clinical result of lowering blood pressure. For example, at location 360 and/or 362 two treatments can achieve the same effect, as the renal nerves 350 are concentrated together (e.g., afferent and efferent renal nerves travel together).

In some embodiments, catheters with ultrasound transducers for treatment at specific locations can be custom designed. For example, a straight catheter 364 with a transducer 368 can be designed for treatment at location 362. For example, a curved catheter 366 can be designed for treatment at location 360 (e.g., by placing a transducer 370 at the curve) and/or at location 358 (e.g., by placing a transducer 372 at the distal end of catheter 366).

In an exemplary embodiment of the invention, the ultrasound energy used to treat the target tissues does not need to be applied directly to the vessel wall. Optionally, the ultrasound energy is applied away from the vessel wall, for example, the transducer is not in contact with the wall.

In an exemplary embodiment of the invention, damage to the intima layer (e.g., endothelium) and/or internal elastic lamina of the vessel wall is prevented and/or reduced. A potential advantage is preventing and/or reducing the risk of adverse clinical outcomes, for example, one or more of, triggering a coagulation cascade, causing a vessel spasm, causing stenosis, blood loss due to injury to the vessel wall.

Exemplary Treatment Device

FIG. 5 illustrates a target tissue being irradiated with ultrasonic energy, in accordance with an exemplary embodiment of the invention. Shown is catheter 1222 inside a lumen 1240 of a blood vessel 1242 (e.g., artery). Optionally, an acoustic element 102 (e.g., part of transducer 300) emits a beam 1228 of ultrasound energy towards a target tissue 1216.

In an exemplary embodiment of the invention, the ultrasonic emission element and/or transducer 300 is capable of relatively high intensity ultrasound output. Optionally, transducer 300 is gas-backed, such as with a bubble of gas. Non-limiting examples of high intensity ultrasound include at least 20 watts/cm², at least 30 watts/cm², at least 50 watts/cm², at least 100 watts/cm² or other smaller, intermediate or larger intensities.

In an exemplary embodiment of the invention, beam 1228 is unfocused, for example, beam does not converged at a point, for example, beam diverges relatively little.

In an exemplary embodiment of the invention, the shape of element 102 is rectangular. Optionally, element 102 is planar. Optionally, a length of element 102 is, for example, about 1 mm, about 2 mm, about 4 mm, about 6 mm, about 8 mm, about 10 mm, or other smaller, intermediate or larger lengths are used. Optionally, a width of element 102 is, for example, about 0.2 mm, about 0.6 mm, about 1.0 mm, about 1.4 mm, about 2.0 mm, or other smaller, intermediate or larger widths are used.

In an exemplary embodiment of the invention, beam 1228 produced by a rectangular acoustic element is relatively straight, spreading an angle of about fifteen degrees relative to the exposed surface of element 102, when measured along the length.

In an exemplary embodiment of the invention, target tissue 1216 is located a distance 1232 away from wall 1226. Non-limiting examples of the maximum distance 1232 of target tissue 1216 that can be treated include 0.5 mm, 1 mm, 2 mm, 5 mm, 10 mm, or other smaller, intermediate or larger distances.

In an exemplary embodiment of the invention, target tissue 1216 is treated by an ultrasound beam 1228 from transducer 300. In an exemplary embodiment of the invention, treating comprises a thermal effect (e.g., heating to above 55 degrees Celsius) and/or a cavitation effect.

The table below illustrates some non-limiting examples of the effect of temperature on nerves over time. The rise in temperature is due to heat sources in general and is not limited to ultrasonic heating.

Temp Histological findings - Article (° C.) Follow up summary Xu & 47 Immediately Schwann cells - disrupted Pollock, after cytoplasmic organelles 1994 treatment Blood vessels - collapsed; endothelia separated from overlying pericytes; swollen endothelia and perivascular oedema in endoneurial capillaries; Axoplasm - ‘watery’ Xu & 47 2 hours after Myelinated axons - degenerating Pollock, thermal 1994 injury Xu & 47 6 hours after Myelin - decrease in diameter Pollock, thermal Myelinated axons - degenerated 1994 injury Myelinated fibers - distended Xu & 47 1 day after Axons - degenerated Pollock, thermal Schwann cells - hypertrophied 1994 injury Xu & 58 immediately Myelin - widened Schmidt-Lanterman Pollock, after incisures; disruption of myelin 1994 treatment lamellae Blood vessels - endothelia separated from overlying pericytes; thrombosed; perivascular oedema Unmyelinated fiber - degenerated Unmyelinated axons - swollen and devoid of organelles Xu & 58 3 days after Nerve fibers - destructed Pollock, thermal 1994 injury Lele, 24-48 Axons -fragmented; nodular appearance; 1963 continuity interrupted; decreased in length Myelin - vacuolated

In an exemplary embodiment of the invention, damage and/or treatment to tissues (e.g., normal, healthy) surrounding target tissue 1216 is reduced and/or prevented. Optionally, treatment and/or damage to a volume of tissue between target tissue 1216 and wall 1226 is reduced and/or prevented.

In some embodiments, contact between an acoustic element 102 of transducer 300 and wall 1226 of vessel 1240, is reduced and/or prevented, for example, by a separation device 1204. Optionally, device 1204 maintains a distance 1218 between element 102 and wall 1226 of at least 1 mm. Optionally, a relatively cool liquid (e.g., blood, injected saline) flows in distance 1218. In an exemplary embodiment of the invention, the liquid cools element 102 and/or wall 1226.

In some embodiments, catheter 1222 comprises at least one transducer 300, positioned for example, on the side, such as inside a window cut into the catheter shaft 1230.

In an exemplary embodiment of the invention, element 102 is cooled. Optionally, cooling occurs by transfer of heat from element 102 to a surrounding fluid such as blood 1220, saline, urine, water, angiography contrast fluids, cerebrospinal fluid, lymph, mucous, stomach acid. Alternatively or additionally, cooling occurs by injection of a volume of a liquid (e.g., saline, radio-opaque dye) through tube 1206, and/or circulation of a liquid through tube 1208. Alternatively or additionally, cooling is increased using an active heat flux, such as a thermoelectric cooler. It should be noted, that herein cooling by blood flow also refers to cooling using other fluids (e.g., saline) in addition to blood, or cooling using other fluids as a substitution for blood cooling.

In an exemplary embodiment of the invention, a temperature sensing element, such as sensor 308, measures and/or estimates the temperature of element 102. In an exemplary embodiment of the invention, sensor 308 measures the temperature of blood that has flowed 1220 over a surface 1224 of element 102. In an exemplary embodiment of the invention, the temperature of the blood that has flowed 1220 over surface 1224 is used as an estimate of the temperature of element 102.

In an exemplary embodiment of the invention, a 6 mm long X 1 mm wide transducer emitting ultrasound energy at an intensity of 100 Watts/square centimeter, is calculated to generate about 11-24 Watts of excess heat (variation according to efficiency of operation) for removal. The amount of heat generated varies linearly with the size of the element and/or the intensity of emitted ultrasound energy.

Decide Amount of Thermal Effect

FIG. 6A is a schematic diagram of a cross section of an artery 600, useful in practicing some embodiments of the invention. The layers of the wall of artery 600, from a lumen 602 outwards are: endothelium 604, internal elastic media 606, media 608, adventia 610 having vasa vosorum 612 embedded therein, peri-adventitia 614, peri-vess (peri-adventitia blood vessels (capillaries)) 616, peri-nerv (peri-adventitia nerve fibers) 618.

In an exemplary embodiment of the invention, one type of target tissue is nerve tissue 620. In some anatomies, nerves 620 surrounded by fat are especially well suited for targeted treatment, for example, as will be discussed with reference to FIG. 7B. Nerve tissue 620 is commonly located in peri-adventitia 614.

In an exemplary embodiment of the invention, the extent of thermal damage is selectable and/or controllable. Optionally, thermal damage is selected to include only the target tissue, for example, thermal damaged nerves 622. Alternatively or additionally, thermal damage is selected to include tissue surrounding the target tissue.

In an exemplary embodiment of the invention, the portion of the target tissue to treat by thermal effect is selected. Optionally, a portion of the target tissue experiences thermal damage and a portion of the same target tissue does not experience damage, for example, as shown with reference to nerve 624. The left side of nerve 624 experienced thermal damage and the right side of nerve 624 did not experience thermal damage. In an exemplary embodiment of the invention, the effect of thermal damage to portion of the target tissue is associated with an unfocused ultrasound beam that is relatively high in acoustic intensity, and diverges a relatively small amount. In some embodiments, a portion of the nerve is treated by directing the ultrasound beam to the desired targeted portion of the nerve. Alternatively or additionally, parameters are selected to treat the portion of the nerve, for example, a thermal effect that starts a first distance away from the intima and ends a relatively closer second distance away from the intima, where the target portion of the nerve falls between the first and second distances, and the portion not to be treated falls between the second distance and the intima.

In an exemplary embodiment of the invention, the extent of the thermal effect to the target tissue is selected, for example, tissues can be partially thermally damaged to the extent that the damage is reversible (e.g., tissue can self regenerate and/or heal).

In an exemplary embodiment of the invention, the functional result of the thermal effect is selected, for example, to achieve a temporary effect (e.g., reversible effect).

In an exemplary embodiment of the invention, the spatial profile of the thermal effect is selectable, for example, the volume of the thermal effect.

FIG. 6B is a cross sectional view, FIG. 6C is a side view and FIG. 6D is a top view illustrating a controllable volume of thermal damage 648 to tissue, for example to a blood vessel wall 640, in accordance with an exemplary embodiment of the invention. Optionally, thermal damage is caused by an ultrasound beam 642 from a transducer 644.

In an exemplary embodiment of the invention, thermal damage is selectable a distance into wall 640 as measured from a lumen 646, for example, zero is set at the boundary of wall 640 and lumen 646. Optionally, thermal damage starts at about a distance “r1” and ends at about a distance “r2”, wherein r1 is greater than or equal to zero and r2>r1. In some embodiments, r2 is greater than the thickness of wall 640, for example, tissues outside of the blood vessel can be thermally damaged.

In an exemplary embodiment of the invention, the volume of thermal damage 648 is selectable, for example, the volume of thermal damage is an area of about “x2−x1” (e.g., measured along the cross section of the blood vessel) multiplied by about “y2−y1” (e.g., measured along the long axis of the blood vessel) multiplied by about “z2−z1” (e.g., measured parallel to the diameter of the blood vessel). Optionally, the volume of the thermal damage is associated with one or more factors, such as the size and/or area of an acoustic element of transducer 644, the tissues in the wall (e.g., the tissues from the intima to the target tissue, as well as the target tissue), and/or the interaction between the tissues and the ultrasonic energy (e.g., attenuation).

In an exemplary embodiment of the invention, the location of thermal damage 648 is selectable. Optionally, an angular location 660 of thermal damage is selectable, for example, in the range of 0-360 degrees, as determined by an arbitrary reference such as on a fluoroscopic image. Alternatively or additionally, a longitudinal location 652 in the artery is selectable, for example, measured in centimeters, as determined by an arbitrary reference such as distance from an arterial branch. Optionally, angle 660 and/or longitudinal location 652 are selected according to the position of transducer 644, for example, rotating transducer and/or longitudinal positioning of transducer 644. Optionally or additionally, the extent of the thermal effect and/or thermal damage is selectable.

In an exemplary embodiment of the invention, a damage axis (e.g., the volume of thermal damage) is aligned with the tissue axis. For example, to cause a clinical effect in elongated nerves such as by thermally damaging them, it is sufficient to treat a section of the nerve as opposed to the entire nerve.

Partial Denervation

In some embodiments of the invention, only partial denervation is desired, for example, it may be desired to reduce the function of the nerves by, for example, 20%, 30%, 50%, 80%, 90% or intermediate or larger amounts. In an exemplary embodiment of the invention, the function of the nerves is measured by the effect on the target tissue controlled by the nerves and/or providing signals to the nerves, rather than by the nerves ability to transmit signals.

In an exemplary embodiment of the invention, it is desirable to maintain some of the natural feedback controls over blood pressure and/or other biological functions, provided by the nerve (e.g., as part of a biological system), albeit, at an attenuated level, for example, to compensate in part or in full and/or overcompensate for a diseased state caused by such feedback. It has, in fact, been found that even partial denervation which only causes a drop of Renal Norepinephrine spillover to about 50% from baseline (e.g., in a diseased patient), still provides a significant drop in blood pressure.

In greater detail. In the kidney, Norepinephrine (NE) is stored only in the renal sympathetic nerve terminals from where it is released in relation to increases in renal sympathetic nerve activity (renal Norepinephrine spillover (NESO)). Thus, it is reasonable to assume that if renal tissue NE content is decreased, then there is less NE in the renal sympathetic nerve terminals available for release and that renal NESO will be decreased somewhat in proportion to the decrease in renal tissue NE content. Thus, in this way, a rough correlation is to be expected between the renal tissue NE content and renal NESO. It is noted that this relationship is not a precise and/or necessarily a linear relationship.

In organ physiology, the assumption is made that if a control mechanism exists, then it is meant to fulfill a vital function, even if it is redundant to other control systems. Thus, the efferent renal nerves are involved in controlling certain renal functions (GFR, RBF, sodium handling, renin release, etc.). Activation of these mechanisms in times of volume depletion (hemorrhage, etc.) can be of value in preserving integrity of body fluid volumes and cardiovascular integrity. The afferent renal nerves sense pain (e.g., due to kidney stone) as well as provide other reflex inputs to the central nervous system that influence systemic sympathetic outflow to the periphery. While it believed that efferent renal nerves grow back and that afferent renal nerves do not grow back, the consequences of total (afferent and efferent) renal denervation over a long time future is not clear and it may be desirable to avoid.

In an exemplary embodiment of the invention, selecting the treatment parameters includes deciding on a desired degree of denervation and/or desired change in NE, for example, a change over time, for example, a change at one day (from denervation), 10 days, 30 days, 90 days and/or intermediate and/or longer times and/or at a plurality of times. Optionally, after a period of time, for example, 1 month or several months, a partial denervation may be repeated (e.g., at one or both kidneys), for example, to achieve a desired results shown by the NE levels (or a marker thereof) not to have been achieved.

Decide Safety Considerations

In an exemplary embodiment of the invention, a margin of safety is selectable.

In an exemplary embodiment of the invention, the extent of thermal damage to tissues (e.g., normal and/or healthy) surrounding a target tissue 650 (e.g., nerve) is selectable. Optionally, volume of thermal damage 648 is approximately a volume of target tissue 650. Alternatively, volume of thermal damage 648 is relatively larger than the volume of target tissue 650.

In an exemplary embodiment of the invention, the volume of normal tissue thermally treated (e.g., in volume of thermal damage 648) surrounding target tissue 650 is selectable, for example, as a margin of safety. A potential advantage is a trade-off between certainty of thermally damaging target tissue 650 and damaging nearby tissue (e.g., healthy and/or normal).

In an exemplary embodiment of the invention, side effects as a result of treatment are selectively reduced and/or prevented by proper selection of treatment parameters. For example, one or more scarring, shrinking and/or spasm of the blood vessel may be reduced such as by a treatment profile that maintains a temperature sufficiently low to achieve a thermal effect while avoiding side effects (e.g., 55 degrees Celsius) and/or for a time period sufficiently long to achieve the thermal effect while avoiding side effects.

Estimate Blood Flow

In an exemplary embodiment of the invention, the rate of blood flow is measured and/or estimated, for example, using one or more methods including, a look-up table of estimated blood flow rates in blood vessels, Doppler, flow sensor, temperature measurement downstream of the transducer (e.g., measuring temperature to estimate if blood flow is sufficient). Optionally, the rate of blood flow as a function of time is controlled, for example, by inflating and/or deflating a balloon upstream from the transducer. Alternatively or additionally, a liquid (e.g., saline, radio-opaque dye) is injected to create flow.

In some embodiments of the invention, the diameter of the catheter is selected according to the desired rate of blood flow. For example, a relatively smaller catheter is selected to provide for relatively greater blood flow, such as a relatively faster rate of blood flow. For example, a relatively larger catheter is selected to provide for relatively slower blood flow. Non-limiting examples of diameters include; 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, or other smaller, intermediate or larger values are used. Optionally, the diameter of the catheter is selected relative to the diameter of the blood vessel, for example, about 20%, 30%, 40%, 50%, 75% of the vessel diameter, or other smaller, intermediate or larger values are used.

FIG. 7A illustrates an exemplary of a simplified estimate of the association between a flow of blood and the location of an area of thermal damage.

The upper part of FIG. 7A shows an ultrasound transducer 706 emitting ultrasound energy 708 at a target tissue 712. Energy 708 travels across a lumen 730 (e.g., of a blood vessel) into a blood vessel wall 710. Energy 708 causes an area of thermal damage 704. Blood flows 702 inside lumen 730.

Without being bound to theory, the lower part of FIG. 7A illustrates an exemplary association between blood flow 702 and the resulting area of thermal damage 704. Thermal damage 704 is hypothesized to occur when the temperature of a tissue reaches 55 degrees Celsius or higher. The temperature in tissues of blood vessel wall 710 is a tradeoff between the tissues being heated by ultrasonic energy 708 (e.g., mechanical friction) and the tissues being cooled by flow of blood 702 (e.g., convection).

Curve 714 is an exemplary illustration of a simplified estimate of the effect of heating of wall 710 due to ultrasonic energy 708 absorption (e.g., attenuation) as a function of distance away from lumen 730. As energy 708 travels through wall 710, it is absorbed, resulting in tissue of wall 710 heating up. Without blood flow 702, the tissues closest to lumen 730 heat up the most and the tissues furthest away heat up the least.

Curve 716 is an exemplary illustration of the cooling effect on wall 710 due to blood flow 702 as a function of distance away from lumen 730. Tissues closest to lumen 730 are cooled relatively more by blood flow 702, and tissues furthest away are cooled relatively less.

Without being bound to theory, if heat generated by ultrasonic energy 708 is removed sufficiently quickly by blood flow 702, the tissues in wall 710 will not heat up enough to achieve a thermal effect. At the point where the heat due to energy 708 is not removed fast enough, the tissue can heat up to 55 degrees, potentially resulting in area of thermal damage 704.

In an exemplary embodiment of the invention, blood flow 702 is taken into account to adjust parameters to treat target tissue 712 and/or to set area of thermal damage 704, for example, by using a look-up table of correlated values and/or using a mathematical formula modeling (e.g., manually by a user, automatically by a software module). Optionally, the intensity profile of energy 708 (e.g., time of treatment, intensity of energy emitted) is selected according to target tissue 712 and/or area of thermal damage 704. Alternatively or additionally, the frequency of ultrasonic energy 708 is selected.

FIG. 7B is an exemplary graph illustrating a simplified estimate of the effects of various tissues absorbing ultrasound energy in obtaining a desired thermal effect, useful in practicing some embodiments of the invention. In an exemplary embodiment of the invention, selecting target tissue for treatment is associated with the ability of the target tissue and/or tissues between the transducer and the target tissues in attenuating ultrasonic energy.

The table below illustrates the ability of different types of tissues to absorb (e.g., attenuate) ultrasound energy. Tissues having relatively higher coefficients of attenuation, heat relatively more.

In an exemplary embodiment of the invention, the relatively values as shown in the table are used to prepare a treatment plan to selectively target tissues. For example, to selectively target connective tissue (α=1.57) surrounding muscle (α=1.09), the treatment plan can consist of bursts of ultrasonic energy separated by gaps without energy transmission. During the bursts, the ultrasonic energy will be attenuated relatively more by the connective tissue resulting in a relatively higher temperature. During the gaps, the ultrasonic energy will be dispersed relatively more quickly by the muscle. The net result of the treatment pattern is that connective tissues will be heated to a thermal effect, while the muscle will not achieve a temperature high enough to be thermally affected.

Material α(dB/(MHz · cm)) Blood 0.2 Fat 0.48 Liver 0.5 Cardiac 0.52 Brain 0.6 Breast 0.75 Muscle 1.09 Connective tissue 1.57 Tendon 4.7 Bone, cortical 6.9

The top part of FIG. 7B illustrates transducer 706 emitting ultrasonic energy 708 into arterial wall 710. The bottom part of FIG. 7B illustrates relative energy 708 absorption by different tissues.

Starting from lumen 730, the layers of wall 710 can be categorized as intima 718, media 720 and adventitia 722. As intima 718 is a single layer of endothelial cells, energy 708 absorption can be assumed to be negligible. Media 720 is primarily muscle, having a relatively low level of absorption. Adventitia is primarily connective tissue, having a relatively higher level of absorption. The attenuation of acoustic energy is inversely related to frequency, for example, a relatively higher frequency results in relatively higher attenuation. In an exemplary embodiment of the invention, an area of thermal damage is associated with relatively higher levels of energy 708 absorption by adventitia 722.

In an exemplary embodiment of the invention, the relative attenuation of energy 708 by tissues is taken into account when deciding on treatment parameters for the target tissue. In some embodiments, the target tissue is nerve 724. Nerve 724 is primarily connective tissue, having a relatively higher US attenuation coefficient. In some embodiments, nerve 724 is selectively targeted for thermal damage.

In some cases, nerve 724 is surrounded by a layer of fat 726. Fat 726 has a relatively lower level of absorption (e.g., attenuation of the acoustic energy) and relatively low level of thermal conductivity (e.g., doesn't transfer the thermal energy). Inventors hypothesize that fat 726 acts as a thermal insulator for nerve 724, trapping the US energy absorbed by nerve 724 (e.g., heat), as the heat dissipation outside fat ring 726 is relatively higher (e.g., relatively lower attenuation coefficient), the outside tissues do not heat up as much. In an exemplary embodiment of the invention, nerve 724 surrounded by fat 726 is selectively targeted for thermal damage. In an exemplary embodiment of the invention, energy 708 causes temperature in nerve 724 surrounded by fat 726 to exceed a threshold, resulting in thermal damage 728 to nerve 724, while tissues surrounding fat 726 are not thermally affected (e.g., damaged).

FIG. 7C is an exemplary graph illustrating a simplified estimate of the effect of the ability of heat removal in obtaining a desired thermal effect, useful in practicing some embodiments of the invention. In an exemplary embodiment of the invention, selecting target tissue for thermal damage is associated with the capacity of heat removal from the target tissues and/or surrounding tissues.

In an exemplary embodiment of the invention, heat removal from tissues in wall 710 occurs from lumen 730. Optionally, the rate of heat removal is variable. Alternatively or additionally, the rate of heat removal is controllable.

In an exemplary embodiment of the invention, heat removal is accomplished by a flow of blood in the lumen. Without being bound to theory, a higher flow of blood results in a higher rate of heat removal. Optionally, the flow of blood in the lumen is selectable and/or controllable, for example, by one or more methods such as, cardiac pacing (e.g., artificially controlling the heart rate), inflating a balloon inside the artery, and/or operating an obstructing structure on the catheter, to at least partially block the flow of blood and/or to direct the flow to the target artery wall.

In an exemplary embodiment of the invention, heat removal is associated with the temperature of the blood in the lumen. Without being bound to theory, a lower blood temperature results in a higher rate of heat removal. Optionally, the temperature of blood is selectable and/or controllable, for example, by injection of a relatively cold liquid upstream from the treatment area (e.g. saline, radio-opaque dye, patient's own blood that has been cooled).

For illustrative purposes, FIG. 7C shows a relatively slow heat removal 740 and a relatively fast heat removal 742 in lumen 730. In some embodiments, slow heat removal 740 results in a thermal damage area 744 that is relatively closer to lumen 730. In some embodiments, fast heat removal 742 results in a thermal damage area 746 that is relatively further away from lumen 730.

Without being bound to theory, the bottom part of FIG. 7C shows that for the same ultrasound attenuation curve 714 (e.g. ultrasound energy 708 produced by transducer 706), a slow removal curve 748 causes thermal damage area 744 relatively closer to lumen 730 as compared with a fast removal curve 750 that causes thermal damage area 746 relatively further from lumen 730.

Adjusting Tissue Properties

In some embodiments of the invention, one or more tissue parameters are adjusted. Optionally, the tissue is adjusted (which affects the tissue parameters) in accordance with one or more treatment parameters, for example, the selected safety profile and/or selected amount of thermal effect. Optionally, parameters are adjusted relatively higher or relatively lower.

In an exemplary embodiment of the invention, adjustment is provided by the controller, optionally using the catheter, for example, to deliver an electrical current or a drug to the artery and/or to the heart and/or other tissue, such as tissue near the artery. Alternatively a separate application device is provided. In an exemplary embodiment of the invention, the adjustment is automatic. Alternatively, the adjustment is in response to a manual control. Optionally, the adjustment is semi automatic, with the controller, for example, modifying the adjustment means to maintain a user-indicated result, such as vessel diameter. In an exemplary embodiment of the invention, the treatment is modified (e.g., automatically, by the controller) in realtime to match the modification and/or so it is applied when the blood vessel properties are within a given window (e.g., timed to thickness changes associated with the pulse wave), even if no intentional adjustments is applied.

FIGS. 7D and 7E illustrate non-limiting examples of adjustments of tissue parameters, in accordance with some embodiments of the invention. FIG. 7D illustrates a relative decrease in tissue parameters; temperature, thickness of vessel wall, diameter of blood vessel, rate of blood flow. FIG. 7E illustrates a relative increase in tissue parameters; temperature, thickness of vessel wall, diameter of blood vessel, rate of blood flow. Catheter 1222 having ultrasonic emission element 300 is located inside blood vessel 1242. Ultrasound is used to treat target tissue 1216 surrounded by tissue 1304. Blood 1302 is flowing through vessel 1342.

In some embodiments of the invention, the temperatures of one or more of blood 1302, surrounding tissue 1304 and/or target tissue 1216 are adjusted, for example, to one or more different temperatures. Optionally, the temperature of one or more tissues is relatively increased (shown as T1), for example, by 0.2 degrees Celsius, or 0.5 or 1 or 2 or 5 or 10 degrees Celsius above body temperature, or other smaller, intermediate or larger values are used. Alternatively or additionally the temperature of one or more tissues is relatively reduced (shown as T2), for example, by 0.2 degrees, Celsius, or 0.5 or 1 or 2 or 5 or 10 or 20 or 30 or 35 degrees Celsius below body temperature or other smaller, intermediate or larger values are used. Non-limiting options of adjusting the temperature include: inserting the patient and/or region of the body into a solution of relatively cooler or relatively hotter liquid, blowing cold or hot gas (e.g., room air) on the patient, infusing relatively cold or relatively hot liquid (e.g., saline) into the patient. Exemplary reasons for changing the temperature of tissues will be described below.

In some embodiments of the invention, the thickness of the arterial wall is adjusted. Optionally, the arterial wall is maintained and/or expanded (if in a contracted state). Optionally or alternatively, the arterial wall is contracted, for example, by about 10%, about 20%, about 30%, or other smaller, intermediate or larger values. The rate of evacuation of heat from surrounding tissues 1304 and/or target tissue 1216 can be related to contraction and/or expansion of the arterial wall. For example, expanding and/or relaxing the arterial wall can cause a dilation of the vasa vasorum, thereby increasing blood flow and the evacuation of heat. For example, contraction of the arterial wall can cause contraction of the vasa vasorum, thereby decreasing blood flow and the evacuation of heat.

In some embodiments, the entire circumference of the vessel is adjusted. Alternatively, an arc of the circumference of the vessel is adjusted, for example, about 10, 15, 30, 45, 60, 90 degrees, or other smaller, intermediate or larger values are adjusted. One part (e.g., arc) of the vessel around the circumference is adjusted, for example, 2, 3, 4 or other smaller, intermediate or larger numbers of areas around the circumference. Optionally, the adjusted areas correspond to the treatment areas.

In some embodiments, a portion of the blood vessel length is adjusted. For example, about 5 mm, about 10 mm, about 20 mm, about 30 mm, about 50 mm, about 100 mm, or other smaller, intermediate or larger values are used. Alternatively, areas substantially larger than the blood vessel itself are affected, for example, an organ, a limb, the entire body, the entire vasculature.

In some embodiments, the volume of the adjusted tissue corresponds to the selected volume of the desired thermal effect. Optionally, the target tissue is within the adjusted tissue. For example, the volume of adjusted tissue is about 100%, 150%, 200%, 500%, 1000%, 10000% of the volume of the desired thermal effect, or other smaller, intermediate or larger values are used.

In some embodiments of the invention, the rate of evacuation of heat from one or more of blood 1302, surrounding tissues 1304 and/or target tissue 1216 are adjusted, for example, by varying amounts. Optionally, the rate of evacuation of heat is relatively increased. Alternatively or additionally, the rate of evacuation of heat is relatively decreased.

In some embodiments of the invention, flow of blood 1302 through vessel 1242 is adjusted. Optionally, a relatively higher rate of blood flow 1302 (shown as long arrows) relatively increases the rate of heat removal. Optionally or additionally, a relatively lower rate of blood flow 1302 (shown as short arrows) relatively reduces the rate of heat removal. The effect of heat removal, such as on the area of thermal damage, has been described with reference to FIGS. 7A-7C.

Non-limiting examples of methods to adjust the rate of blood flow 1302 include:

-   -   Increasing or decreasing the cardiac output, for example, by         artificially pacing the heart (e.g., external pacemaker) to a         relatively higher or relatively lower rate, for example, to 120,         150, 180, 200 beats per minute or other smaller, intermediate or         larger values.     -   Dilating blood vessel 1242 (shown as d1), such as by         administration (e.g., into the vasculature) of vasodilatory         agents such as nitrates (e.g., nitroglycerin) and/or agents to         relax the muscles of arterial wall 1242, such as muscle         paralyzing agents such as botulinum (blocks release of         acetylcholine). Agents can be delivered locally and/or         systemically. Electricity can also be applied in a pattern         and/or settings (e.g., long DC signal) that relaxes the arterial         wall.     -   Constricting blood vessel 1242 (shown as d2), such as by         administration of vasoconstricting agents such as alpha-1         agonists (e.g., phenylephrine), by applying an electrical         current to cause muscle contraction in arterial wall 1242,         and/or by mechanically agitating tissues (e.g., traumatizing) to         cause constriction.

In some embodiments of the invention, the absorption to applied ultrasound energy of one or more of blood 1302, surrounding tissues 1304 and/or target tissue 1216 are adjusted, for example, by varying amounts. Optionally, the absorption is relatively increased (shown as TR). A non-limiting example of relatively increasing the absorption to ultrasound is by injecting a material that absorbs ultrasound energy to a relatively higher degree, such as microbubbles.

In some embodiments of the invention, tissue properties are adjusted in accordance with the selected safety parameters, for example, to relatively increase the margin of safety. Optionally, the rate of heat removal from surrounding tissues 1304 is relatively increased, for example, as described herein. Alternatively or additionally, the temperature of tissues 1304 is relatively reduced, for example, as described herein. A potential advantage of increasing the rate of heat removal and/or reducing the temperature is reducing thermal damage to surrounding tissues 1304, for example, as described with reference to FIGS. 7A-7C.

In some embodiments of the invention, tissue properties are adjusted in accordance with the selected thermal damage profile, for example, to relatively increase the area of thermal damage. Optionally, the ability of surrounding tissues 1304 to absorb ultrasound energy is relatively increased, for example, as described herein. Alternatively or additionally, the temperature of tissues 1304 is relatively increased. A potential advantage of increasing the temperature and/or acoustic absorption is increasing the thermal effect of the applied ultrasonic energy, for example, as described with reference to FIGS. 7A-7C and/or FIG. 9. For example, if the tissue temperature is increased and/or the rate of heat removal is decreased, the thermal effects resulting from an amount of acoustic energy can be relatively increased.

Selecting parameters—example of choosing catheter (Frequency) According to Treatment

FIG. 8 is an exemplary illustration of a simplified estimate of the effect of frequency of ultrasound energy on an area of thermal damage, in accordance with an exemplary embodiment of the invention.

The top part of FIG. 8 illustrates an ultrasound transducer 806 emitting ultrasound energy towards an arterial wall 812. Non-limiting examples of the ultrasound energy include 20 Mhz ultrasound energy 808 and/or 10 Mhz ultrasound energy 810.

The bottom part of FIG. 8 illustrates the attenuation of energy 808 and/or 810 by the tissues of wall 812. As illustrated by the table in the section “ESTIMATE BLOOD FLOW”, attenuation of ultrasound energy by tissue is inversely proportional to frequency. An exemplary attenuation graph for 20 Mhz 816 shows relatively higher attenuation relatively closer to a lumen 818. In some embodiments, an area of thermal damage 802 is relatively closer to lumen 818. An exemplary attenuation graph for 10 Mhz 814 shows relatively lower attenuation as a function of distance from lumen 818. In some embodiments, an area of thermal damage 810 is relatively further from lumen 810.

In an exemplary embodiment of the invention, the frequency of ultrasound energy used for selectively targeting tissue is selected according to the treatment plan. For example, target tissue relatively further from the lumen and/or from the intima layer is selectively treated by using a relatively lower frequency of ultrasound energy.

In an exemplary embodiment of the invention, the frequency of the ultrasound energy used for treatment is selected, for example to be about 5 Mhz, about 8 Mhz, about 10 Mhz, about 15 Mhz, about 8 Mhz-15 Mhz, about 20 Mhz, about 10 Mhz-20 Mhz, about 30 Mhz, or other smaller, intermediate or larger frequencies. IN some cases, et frequncy will be substantially narrow band, for example, les sthan 30%, 20%, 10%, 5% of the application frequency. Optionally or alternatively, a wide band or multi frequency signal is used, for example, with 2, 3, 4, 5 or more discrete frequencies and/or with a range of, for example, 1 Mhz, 3 Mhz, 5 Mhz or smaller or intermediate widths.

In an exemplary embodiment of the invention, for example for renal denervation, a lower frequency may be used to achieve a higher reduction in norepinephrine levels.

In an exemplary embodiment of the invention, the signal parameters are selected according to a desired functional effect, in addition to or instead of according to a desired structural effect (e.g., tissue ablation).

In an exemplary embodiment of the invention, a catheter is selected according to the frequency of the selected ultrasound energy. Optionally, the acoustic element on the transducer is designed to vibrate at the treatment frequency. For example, the thickness of the acoustic element is related to the expected frequency of vibration of element, optionally linearly related, for example, a thickness of 100 micrometers for a frequency of 20 Mhz, a thickness of 200 micrometers for a frequency of 10 Mhz.

Selecting Parameters—Choosing an Ultrasonic Intensity Profile According to Treatment

FIG. 9 is an exemplary illustration of a simplified estimate of the association between an ultrasonic intensity profile and thermally damaged areas, useful in practicing some embodiments of the invention.

In an exemplary embodiment of the invention, the ultrasonic intensity profile for treatment is selected. Optionally, the ultrasonic intensity profile is related to the ultrasonic intensity emitted by the acoustic element (e.g., in watts per square centimeter) over time (e.g., in seconds), for example, relatively longer times relatively increase the ultrasonic intensity profile, for example, relatively higher acoustic intensities relatively increase the ultrasound intensity profile. Optionally or additionally, the ultrasonic profile is selected to vary over time. In some embodiments, the ultrasonic profile is associated with the total amount of ultrasonic energy delivered to the tissues. In some embodiments, the profile is substantially a temporal square wave. Optionally or alternatively, the profile is substantially a spatial square wave (e.g., sharp cut-offs at the edges of the beam), in one or two dimensions.

FIG. 9 shows an ultrasound transducer 902, emitting ultrasonic energy at various intensity profiles, for example, a relatively low intensity profile 904, a relatively medium intensity profile 906 and/or a relatively high intensity profile 908.

In some embodiments, the area of thermal damage begins relatively far from an intima 916, for example, at a peri-adventitia 918. In some embodiments, the area of thermal damage increases towards the intima with relatively increased ultrasonic intensity profiles.

In an exemplary embodiment of the invention, tissues relatively closer to the blood cool relatively faster. In an exemplary embodiment of the invention, a treatment plan comprising of a series of pulses with a delay between the pulses will have a greater cumulative effect away from the wall. In an exemplary embodiment of the intervention, a treatment plan of pulses with delays causes a thermal effect to tissues relatively further away from the wall, without causing a thermal effect to tissues relatively closer to the wall.

In an exemplary embodiment of the invention, the extent of thermal damage is settable according to the ultrasound intensity profile, such as 904, 906 and/or 908. For example, thermal damage is localized to target tissue 910 (e.g., no damage to surrounding tissue). For example, an area of thermal damage 912 extends somewhat beyond target tissue 910. For example, a relatively large area of thermal damage 914 extends a relatively larger area beyond target tissue 910.

In an exemplary embodiment of the invention, the extent of thermal damage is selected to not reach intima 916.

Insert Catheter

In an exemplary embodiment of the invention, catheter 1222 (e.g., as shown in FIG. 5) in inserted into the body of a patient. Standard vascular access methods can be used, for example, from the femoral artery. Optionally, catheter 1222 is threaded using a guidewire 1202 (e.g., over the wire, rapid exchange, “buddy” wire) to the target treatment site (e.g., an artery such as the iliac, renal, carotid, aorta) under image guidance, such as fluoroscopy. Alternatively or additionally, catheter 1222 is directed inside a guiding sheath, for example to protect the ultrasound transducer from mechanical damage during delivery to the target site. Alternatively or additionally, catheter 1222 is directed inside a guiding catheter.

In an exemplary embodiment of the invention, catheter 1222 is guided during delivery using imaging, for example fluoroscopic image.

Referring back to FIG. 5, in an exemplary embodiment of the invention, element 102 on catheter 1222 is prevented from contacting vessel wall 1226, for example, by using separation device 1204. Details about separation device are provided with reference to attorney docket number 50824, incorporated herein by reference in its entirety. Optionally, element 102 contacts wall 1226 if treatment parameters are set and/or adjusted accordingly, for example, if element 102 is sufficiently cooled and/or if the intensity profile is reduced.

In an exemplary embodiment of the invention, distance 1218 (between element 102 and wall 1226) does not have to be taken into account for setting treatment parameters. Optionally distance 1218 varies during treatment. In some embodiments, the attenuation of ultrasonic beam 1228 by blood flow 1220 is relatively insignificant.

A potential advantage of preventing contact between element 102 and wall 1226 is reducing or preventing thermal damage to the endothelium, basal membrane and/or internal elastic lamina.

In some embodiments of the invention, catheter 1222 includes one or more elements to move transducer 300. Optionally, the element is a piezoelectric element that can be vibrated by applying electrical power. Alternatively or additionally, the element moves transducer 300 for relatively fine positioning, for example, an electrically controlled motor. In some embodiments, the element vibrates and/or moves transducer 300 to position the strongest part of the ultrasound beam at the target tissue.

In some embodiments the controller can be calibrated according to the expected intensity profile of the produced ultrasound beam, for example, the controller vibrates and/or moves transducer 300 in order to obtain a desired position for thermally affecting the tissues.

Treat

FIG. 10 is a flow chart of monitoring during treatment, in accordance with an exemplary embodiment of the invention. In some embodiments, monitoring is a type of feedback associated with the parameters affecting treatment.

At 1002, the target tissue is treated. The ultrasound transducer emits ultrasound energy towards the target tissue at the selected acoustic intensity profile and/or at the selected frequency.

In an exemplary embodiment of the invention, the target tissue can be treated according to the selected treatment plan (e.g., acoustic intensity profile, frequency) without requiring monitoring and/or feedback.

Optionally, at 1004, monitoring of the treatment is performed.

In some embodiments of the invention, monitoring occurs at the same time as treatment is occurring (e.g., in parallel with the treatment). Alternatively or additionally, treatment (e.g., transmission of ultrasonic energy) occurs in pulses separated by a delay, with the monitoring occurring during the delay. Optionally, monitoring is carried out continuously during the entire treatment.

Optionally, at 1006, the environment surrounding the treatment procedure is monitored. In some embodiments, changes in environmental conditions affect the treatment if the treatment parameters remain unchanged. For example, if blood flow is increased without changing the treatment parameters, the treatment may not be effective due to the increased rate of cooling. In some embodiments, changes in environmental conditions are taken into account when adjusting treatment parameters, for example, if an increase in blood flow is detected, the intensity profile is increased accordingly to achieve the desired effect in the selected tissues.

In some embodiments, the temperature of the blood flow is monitored, for example, by a sensor placed downstream from the transducer.

Optionally, at 1008, the integrity of the transducer is monitored. In some embodiments, changes in the integrity suggest one or more causes such as blood clots on the transducer, overheating of the transducer, mechanical damage. In some embodiments, changes in the integrity of the transducer are monitored to prevent adverse events. Optionally, the treatment parameters are adjusted according to the integrity. For example, if the transducer comes closer to the wall or contacts the wall, potentially the intima can overheat, resulting in thermal damage to the intima if the treatment parameters are not adjusted accordingly (e.g., increased cooling, reducing the intensity profile).

In some embodiments, the integrity of the transducer is monitored by measuring changes in the impedance, for example, a change greater than 3%, 5%, 10%, 20%, or other smaller, intermediate or larger percent changes.

In some embodiments, the integrity of the transducer is monitored by measuring the distance from the transducer to the arterial wall (e.g. to the intima). Optionally, the distance is measured by a returning echo. Alternatively or additionally, the distance is measured on x-ray images.

Feedback

In some embodiments of the invention, acoustic energy is applied to the target tissue in an open loop manner. For example, the target is set and the target is met, without using feedback. Alternatively, acoustic energy is applied to the target tissue in a closed loop manner, such as with feedback.

In some embodiments, feedback is a measure of the physical effect of the treatment on the tissue. Optionally or alternatively, feedback is a functional measurement. In some embodiments, feedback is provided on the transmission of the energy and/or parameters of the emitter and/or catheter (e.g., distance), in addition to or instead of on the target tissue. While, in an exemplary embodiment of the invention, feedback is during the procedure, possibly during a single application of energy (e.g., within less than 30 seconds), in some embodiments, feedback is on longer time scales, such as 1-3 minutes (e.g., between applications and/or after a set of applications is provided) or days or more.

FIG. 11 is a flow chart showing optional functional feedback associated with treatment, in accordance with an exemplary embodiment of the invention.

Optionally, at 1102 feedback is obtained about the results of the treatment.

Optionally, at 1104, functional feedback is obtained about the effect of treatment on tissues. Optionally, imaging is performed of the target tissue to detect and/or estimate the extent of therapy. Alternatively or additionally, imaging is performed of the surrounding tissue to detect and/or estimate the extent of damage (e.g., margin of safety). In some embodiments, some changes (e.g., due to denaturation of collagen) are detected as they happen. In some embodiments, some changes are detected after a period of time (e.g., several days), for example, anatomical changes secondary to the inflammatory response, such as fibrosis.

In some embodiments, imaging is performed by the using the same ultrasound transducer used for treatment, for example, by treating at a first treatment frequency for a period of time, then imaging at a second diagnostic frequency for another period of time (e.g., analyzing the ultrasonic echoes returning from the tissues). Alternatively or additionally, the same ultrasound transducer is used, but with different electrodes which separate the transducer into an imaging region and a treatment region. Alternatively or additionally, one or more acoustic elements are used, for example, one element for imaging and one element for treatment.

In some embodiments, one or more other imaging modalities are used instead or in addition to the element, such as CT, MRI, x-ray.

One or more non-limiting examples of ultrasound imaging methods for feedback include,

Measuring the ultrasonic attenuation of the target tissues, for example, as described by Damianou et al, J Acoust Soc Am. 1997 July; 102(1):628-34, incorporated herein by reference in its entirety. Damianou found that the rate at which the thermal dose was applied was associated with the total attenuation absorption, for example, relatively lower thermal dose rates resulted in relatively larger attenuation coefficients. In some embodiments, the intensity profile that is applied to the target tissues is estimated by measuring the attenuation coefficient and/or the absorption. Optionally, the measurements are compared to expected values according to the set intensity profile. Optionally or additionally, the intensity profile is adjusted relatively higher or relatively lower according to the comparison, for example, to achieve the resulting thermal damage to the target tissue.

Measuring the ultrasound attenuation coefficient and/or backscatter power for example, as described by Worthington, A. E., et al, Ultrasound in Med. & Biol., Vol. 28, No. 10, pp. 1311-1318, 2002, incorporated herein by reference in its entirety. Worthington found that the attenuation coefficient and/or backscatter power increased with relatively higher temperatures. In some embodiments, the temperature of the target tissues is estimated according to the attenuation coefficient and/or backscatter power. Optionally, the temperature of the tissue is compared to the temperature range and/or threshold required to achieve a desirable effect in the tissues (e.g., collagen denaturation above 55 degrees Celsius). Optionally or additionally, the intensity profile is adjusted relatively higher or relatively lower according to the comparison, for example, to achieve the target temperature in the target tissue.

Optionally, at 1106, feedback consists of clinical effects, for example, desired clinical effects, adverse clinical effects, lack of clinical effects.

In some embodiments, clinical measurements are used as feedback. For example, the results of renal denervation to treat persistent hypertension can be measured by one or more of, blood pressure, norepinephrine spillover, norepinephrine levels, renal artery blood flow.

In some embodiments of the invention, the distance from the acoustic element to the arterial wall is measured, optionally continuously measured. Optionally, the distance is measured using the acoustic element itself, for example, as described in co-filed PCT applications attorney docket numbers 52345 and/or 52342, incorporated herein entirely by reference. In some embodiments, the distance is used as feedback to prevent high power operation of the acoustic element while touching the arterial wall, for example, if the distance is measured to be zero (e.g., contact) or relatively close to contact (e.g., 0.1 mm, 0.3 mm or other smaller, intermediate or larger distances), the power to the transducer can be reduced and/or shut off. A potential advantage of measuring the distance using the element is a relatively more accurate measurement of the distance as compared with measuring the distance from angiographic images.

Adjust

In some embodiments of the invention, monitoring of the treatment and/or feedback of the treatment can increase the level of control of the treatment (e.g., in real time, overall effect over several treatment sessions). Optionally, desired clinical results are achieved by the treatment.

In some embodiments, data from feedback and/or monitoring is used to adjust treatment parameters (e.g., frequency, ultrasonic intensity profile), for example, by a look-up table (e.g., stored in a memory), calculations, trial and error (e.g., slowly changing a parameter and/or monitoring changes). Optionally, parameters are adjusted manually (e.g., by a user) using an interface coupled to a controller. Alternatively or additionally, parameters are automatically adjusted, such as by a software module of controller.

One or more non-limiting examples of adjustments include, increasing the treatment, reducing the treatment, stopping the treatment.

A non-limiting example to illustrate the concept of adjusting variables according to measurements is provided:

A patient with resistant essential hypertension was proposed treatment by a renal denervation procedure. A renal nerve surrounded by fat located about 4 mm away from the renal vessel wall in the peri-adventitia was targeted for thermal effect. A catheter designed for a frequency of 10 Mhz was selected (e.g., due to the relative distance away from the wall) and an initial intensity of 30 watt/cm̂2 was selected based on standard blood flow rates expected (e.g., according to a look-up table of patient profiles). The catheter was inserted into the renal artery. A pulse of duration 1 second was used to initially treat the vessel wall for calibration purposes. Imaging results indicated that the area of thermal effect was located 15 degrees clockwise, and 5 mm away from the wall. Based on the results, the catheter was manually rotated 15 degrees towards the target. Treatment started again, using a pulse of 30 seconds duration. About 5 seconds into treatment, the cardiac output of the patient suddenly increased, causing a 50% increase in the rate of blood flow through the renal artery. The controller automatically increased the intensity profile to 40 watt/cm̂2 to offset the increased cooling rate of the tissue wall by the blood. Another calibration pulse of 1 second was applied. Imaging indicated that the nerve was being thermally damaged. Treatment was stopped after 22 seconds, once imaging results indicated that the nerve was fully damaged, along with a tissue margin around the nerve of at least 0.5 mm. The patient was followed in clinic for several weeks to verify the expected treatment effect of a reduction in blood pressure.

In some embodiments of the invention, treatment is synchronized (e.g., at a same time or otherwise timed thereto, such as at a delay after or before) to the adjustments, for example, as will be described at the end of the section “EXEMPLARY DEVELOPMENT OF AN EQUATION—Part B”

Examplary Treatment Protocols

The table below describes some possible treatment protocols, in accordance with some embodiments of the invention. Optionally, the ‘Thermal Effect Location’ and/or related ‘Information” is determined by imaging, for example, as described in the section “FEEDBACK”. Optionally, action is taken, such as based on the “Information”, for example, by the ‘Cardiologist’ and/or by the ‘System’ (for example, the controller, such as using software stored thereon containing the ‘algorithm’). Details related to ‘Action’ can be found for example in the section “ADJUST”.

Table of Some Possible Treatment Protocols

Thermal effect Action: Action: location Criteria Subject Information Cardiologist System/algorithm Minimal Minimal Thermal Thermal Reduce If distance <1- system distance of 1 mm effect effect energy- stops excitation thermal effect location area/volume change If distance >10- system from artery during treatment alerts- thermal effect is lumen treatment parameters or too far duration Maximal Maximal Thermal Thermal If distance >15- system distance of 15 mm effect effect stops excitation thermal effect location area/volume from artery during lumen treatment Rate of Thermal Rate of Reduce If (maximal − minimal thermal effect effect thermal effect energy- distance) difference is formation location formation change higher than 2 mm/sec- during treatment system stops excitation treatment parameters or duration Enable If (maximal − minimal treatment distance) difference is lower than 2 mm/sec- system enables excitation Location Thermal Thermal Decision- Up to 50% of artery along the effect effect width Continue length-system alert for artery location in artery Adjust cardiologist decision post length Sufficient treatment Location in Thermal Thermal Decision- Up to 50% of artery the artery effect effect width Continue circumference -system circumference location in artery Adjust alert for cardiologist post circumference Sufficient decision treatment Minimal Minimal Thermal Thermal Decision- If thermal effect is too distance of 1 mm effect effect Repeat close to lumen (<1 mm)- thermal effect location area/volume Adjust system suggests from artery post Sufficient cardiologist to add extra lumen treatment anti-coagulation treatment Maximal Maximal Thermal Thermal distance of 15 mm effect effect thermal effect location area/volume from artery post lumen treatment

The following table shows exemplary activities by the controller and/or operator in various conditions, in accordance with some embodiments of the invention, base on the distance between the ultrasound emitter and the wall. Such distance can be measured, for example, using an external system (e.g., angiography or ultrasound), by processing signals received by the emitter or by a separate ultrasonic element.

Distance (calculated/ Value System/ measured) (mm) Subject Criterion Cardiologist algorithm Distance <1.4   Catheter >1 * Change GC (guide * System alert- measurement position catheter) position short distance before before * Change US * System disables treatment treatment transducer angle excitation until * Change US distance is changed transducer position according to along the artery criterion >1 Catheter >1 Enable excitation Enable excitation position before treatment >5 Catheter 1 < x < 5 Too large distance: System alert- position Confirm possible bifurcation, change before bifurcation or US transducer treatment dislocation with position contrast injection and angiography and move US transducer 1 > x > 1.3 Catheter >1 Unreliable distance- Angle position Confirm US between before transducer angle with US treatment contrast injection and transducer angiography: and artery Change GC position wall is larger than 10° >1.3 Catheter >1 Enable excitation Enable excitation Angle position between before US treatment transducer and artery wall is larger than 10° (diagonal) Distance <1 Catheter >1 Change GC * System alerts- short measurement position position and distance during during complete * System stops treatment treatment treatment excitation until distance is changed according to criterion 0.7 < x < 1 Catheter >1 Consider to stop System alert- position excitation and shortening distance during improve position treatment before completing treatment   1 < x < 5 Catheter >1 Enable excitation Enable excitation to position to end end during treatment Decreasing Catheter >1 Possible blood System alert- decreased distance position vessel constriction distance during due to treatment- treatment consider stop and nitroglycerin infusion >5 Catheter >1 System disabled Sudden position movement during treatment Vessel blood Repetitive Pulsation Calculated blood pulsation changes- detection pulsation: analysis Maximal before If normal, enable position to treatment excitation minimal position No differences Pulsation Possible no circulation: System alert- between detection * Validate flow by no pulsation, Maximal before contrast injection and possible position to treatment angiography constriction minimal * If needed- infuse with position nitroglycerin or cold saline distance >1 Pulsation >1 * Validate flow by System alert- But no detection contrast injection and no pulsation, pulsation before angiography possible detection treatment * If needed- infuse with constriction nitroglycerin or cold saline Distance 1^(st)- <1 Artery Possible constriction: System alert- measurement, 2^(nd)- <1 diameter * Confirm by contrast possible rotate 180°, evaluation injection and constriction: distance angiography Disable measurement * If needed- inject excitation nitroglycerin and treat Distance <3 Artery * Check if US transducer System alert- measurement diameter is located in the correct possible in 4 angles evaluation artery- using contrast constriction: (90°)- artery injection and Disable diameter angiography excitation calculation * Check for local constriction * Possible- Nitroglycerin injection   3 < x < 8 Artery Enable excitation Enable diameter excitation evaluation

In an exemplary embodiment of the invention, both kidneys (e.g., renal arteries, renal nerves) are treated. However, this need not be the case. For example, in a follow-up treatment, possibly only a single kidney is treated. Optionally or alternatively, if one kidney is known to be more diseased, that is treated more (e.g., this is a reason for providing a treatment which is asymmetrical between kidneys, this may be done for other reasons as well). Optionally or alternatively, different kidneys are treated a different amount. Optionally, one kidney is intentionally undertreated so as to allow increasing treatment thereof, at a later time.

Potential Advantages of Some Embodiments

Further details of the system described herein can be found in the related applications. For example, “ULTRASOUND EMISSION ELEMENT” (attorney docket no. 52344) describes an ultrasound emission element. For example, “AN ULTRASOUND TRANSCEIVER AND USES THEREOF” (attorney docket no. 52345) describes a method for feedback and control. For example, “AN ULTRASOUND TRANSCEIVER AND COOLING THEREOF” (attorney docket no. 52346) describes cooling of the ultrasonic element. For example, “SEPARATION DEVICE FOR ULTRASOUND ELEMENT” (attorney docket no. 52348) describes preventing contract between the ultrasonic element and the blood vessel wall. For example, “ULTRASOUND TRANSCEIVER AND USES IN DETECTION” (attorney docket no. 52342) describes ultrasonic imaging.

Some embodiments have one or more of the following exemplary advantages:

-   -   Relatively faster treatment, for example, a treatment duration         of 5-30 seconds per treatment region, or other smaller, larger         or intermediate ranges can be used.     -   Relatively small number of treatment regions per artery for         renal denervation, for example, 1 treatment region, 3 treatment         regions, 4 treatment regions, 6 treatment regions, 8 treatment         regions or other smaller, intermediate or larger number of         regions are used.     -   Remote and/or localized effect, for example,         -   Accurate control of the thermal effect and/or location, such             as good control on the location and/or size of the artery             tissue damage by therapeutic parameters.         -   Ability to treat relatively large continuous areas in the             arterial wall.         -   A treatment option for short artery stumps and/or for short             total treatment durations (e.g., 5-10 minutes vs 20 minutes             for RF treatments).         -   The thermal effect volume in the tissue is relatively far             from the transducer face (e.g, media, adventitia,             vasa-vasorum, peri-adventitia, adventitia nerves,             peri-adventitia nerves, peri-adventitia capillaries).         -   Targeting tissues in varying distances from the transducer             face according to treatment parameters. For example,             applying the thermal effect in tissues located about 5 mm or             more from the lumen wall (e.g., intima layer). A relatively             far effect is relevant for example, for achieving peripheral             nerves blocks from inside the peripheral arteries.         -   Non-targeted tissues on the beam path to the target tissue             are not damaged and/or are selectively damaged (e.g.             according to a margin of safety), for example, the             endothelium, basal membrane and/or internal elastic lamina.         -   Possibility for varying levels of thermal modulation of the             target tissue. For example, partial damage to nerves and/or             other target tissues, in a controlled manner and different             effect levels. Potentially, partial nerve injury can be             controlled, that might lead to nerve recovery, either             partially or entirely.     -   Tissue selectivity, for example, highly selective remote thermal         effect in nerve bundles, such as nerves that are covered with         thick fat tissue. For example as used in a Renal Denervation         procedure in the Renal Artery ostium.     -   Treatment features suitable for Renal Denervation include:         -   The ability to work very close to the renal artery ostium,             for example, <10 [mm], or other smaller, intermediate or             larger values.         -   The ability to work in short arteries, for example, <20             [mm], or other smaller, intermediate or larger values         -   The ability to work in small arteries, for example, 4-3             [mm], or other smaller, intermediate or larger values     -   Safety issues         -   Relatively safer treatment.         -   The temperature of the blood that flows over the ultrasonic             transducer can be controlled to not exceed a temperature             threshold of 50 degrees Celsius (or other smaller,             intermediate or larger numbers) while working in the maximal             allowed operation intensity level, for example, 50 [W/cm̂2],             or other smaller, intermediate or larger intensity levels.         -   The temperature of the blood that flows over the ultrasonic             transducer can be controlled to not exceed a temperature             threshold of over 43 degrees Celsius (or other smaller,             intermediate or larger numbers), for example, while working             in the therapeutic operation intensity level 30 [W/cm̂2], or             other smaller, intermediate or larger intensity levels. In             some embodiments, there is no need to add external cooling             such as by saline injection.         -   The therapeutic treatment on the blood vessel wall is done             with no mechanical contact with the vessel wall, thereby             reducing or eliminating the danger of damaging the vessel             wall or disrupting any pathologies on the wall (e.g.,             atherosclerotic plaques). For example, reducing the risk of             arterial perforation and/or mechanical damage that might             cause a narrowing in the vessel, plaque tear and/or emboli.         -   Localized and/or controlled effects specifically in the             targeted treatment volume, preventing and/or reducing             non-controlled energy effects in other tissues.         -   Blocking of the blood flow during the treatment is optional,             and in some embodiments, is not required.         -   Treatment of a single artery location (e.g., longitudinally)             in one or more circumferential directions, potentially,             significantly reducing and/or preventing stenosis.         -   Preventing and/or reducing damage to the artery due to             repeating treatment 2-3 times (or more) at the same axial             position/radial direction, such as due to a mistake.         -   Prevent and/or reduce interference with implanted electronic             medical devices (e.g., pacemakers, defibrillators).         -   Clinical implications, for example, relatively lower pain             during treatment as a result of relatively faster blocking             of nerves, with no electric excitation of the target nerve             and/or no effect on other nerves. Potentially reducing             sedation and/or anesthesia.     -   Relatively shallow learning curve, as leverages existing         operator skill sets.     -   Many applications and/or ability to treat a wide range of         clinical disorders.     -   Treatment option for a wide range of patients, such as high risk         populations, for example as those suffering from vascular         pathologies. Ability to treat in arteries with plaques and/or         stents.     -   Ability to obtain a partial clinical effect (vs. complete         effect). Potentially suitable for patients with milder disease,         such as mild hypertension.     -   Feedback availability during treatment, such as information on         the direction and location of the applied energy, catheter and         the therapeutic catheter tip:         -   Easy control capability and a clear direction and location             of the ultrasonic ray and/or catheter location to carry out             treatment, such as according to the ultrasonic echo             reflection analysis.         -   Ability to control the circumferential direction of the             artery tissue damage.         -   Continues information (e.g., ultrasonic measurement) on the             position of the catheter tip, such as from the artery wall             during treatment.         -   Automatic detection of unwanted and/or risky movement of the             catheter during treatment.

Alternative Ways to Determine Desirable Parameters

In some embodiments of the invention, trial and error is used to figure out at least some parameters. For example, an initial set of parameters estimated to cause a relatively small area of thermal damage can be applied to the target tissue. Alternatively, thermal damage is applied to a region that would not be affected by the small area of thermal damage. Based on the resulting area and/or volume of thermal damage caused by the parameter settings (e.g., according to imaging), one or more settings can be adjusted to achieve a desired effect in the target tissues. Such a process can be followed iteratively until the desired effect is achieved. Such a process is potentially useful in certain situations, for example, if the rate of blood flow is unclear.

In some embodiments of the invention, one or more equations (e.g., a simplified physical and/or mathematical model) are developed for obtaining at least some parameters, for example, as described in detail in the sections “EXEMPLARY DEVELOPMENT OF AN EQUATION” parts A and/or B. In some embodiments, the equations are used to derive parameters according to experimental results. In some embodiments, different equations are developed for different experiments, such as for targeting different types of tissues in different anatomical areas. In some embodiments, parameters are extrapolated based on experimental results.

Exemplary Development of an Equation—Part A

Inventors followed the process as described in FIGS. 1A and/or 1B to conduct experiments in 10 pigs (e.g., results displayed with reference to FIG. 12A). Experiments were performed using a catheter having a diameter of 3 mm. The data collected from the process was analyzed and turned into parameters that affect treatment; the intensity of ultrasound energy, the frequency of ultrasound energy, and the flow rate of blood in the artery. An equation was developed associating the parameters with the resulting area of thermally damaged tissue, such as the minimum radial distance from the artery wall.

The equation is based on the results of the conducted experiments that showed the thermal effect initiating about 3 mm from the intima, in the most distant location of the peri-adventitia. As the acoustic intensity profile increased, the thermal effect increased towards the intima. The experiments were conducted for a period of about 30 seconds. The equation can be adapted for other time periods in a similar manner.

The function that associates the radial distance (the distance from the arterial wall to the start of the thermally damaged area) to the ultrasound treatment parameters is:

x(f,I) [mm]=(C6+a*Exp(flow*b)−C2*log(C3*I [W/cm̂2]))/(C4*f [MHz]+C5)

Where:

I=Excitation intensity [w/cm̂2]

f=Working excitation frequency [MHz]

x=Minimal radial distance from the artery wall [mm]

flow=blood flow rate in the artery [ml/min]

Calculated coefficients in order to adjust the model assumptions, neglects and unknown variables to the experimental results:

a=3.7 (2 . . . 4)

b=−1134(−2500 . . . 0)

C2=93 (90 . . . 100)

C3=2.2 (1 . . . 4)

C4=2.1 (1 . . . 4)

C5=47.4 (45 . . . 50)

C6=400 (0 . . . 1000)

*the numbers in ( . . . ) are the limits of the parameters estimation based on the results of the experiments conducted.

The physical model (for parts A and/or B, below) is based on several assumptions and/or simplifications. The Arrhenius thermal damage equation was used as the basis for estimating the thermal damage area in the artery wall, using a time value of 30 seconds and an effective temperature higher than 55 degrees Celsius. The blood flow in the artery was assumed to be exponentially related to cooling of the artery wall by convection.

The equations were developed by plotting the experimental results (e.g., as summarized in FIG. 12A for the renal arteries (shown in FIG. 13A) and for the carotid arteries (shown in FIG. 13B). The plots graphically illustrate the extent of thermal damage (e.g., the distance from the intima to the start of the damage on the ‘y-axis) as a function of the intensity of the applied acoustic energy (on the ‘x-axis) and as a function of the frequency of the applied acoustic energy (on the ‘z-axis’). The coefficients of the equation were adjusted in order to align the equation to the plots.

Exemplary Development of an Equation—Part B

In another set of experiments, inventors followed the process as described in FIGS. 1A and/or 1B to conduct experiments in 12 pigs (e.g., results shown in FIGS. 12B-12D). Experiments were performed using a catheter having a diameter of 2 mm, at frequencies of 10 Mhz and/or 20 Mhz. Ultrasound was emitted at intensities ranging from 10-35 watt/cm², for time periods ranging from 10-30 seconds. The anatomical target sites were the left and/or right renal arteries.

FIG. 12B summarizes the experimental data for an ultrasound emission frequency of 10 Mhz. FIG. 12C summarizes the experimental data at 20 Mhz. FIG. 12D shows graphs visually displaying the data of FIGS. 12B-12C.

FIG. 12E illustrates variables describing the resulting area of thermally damaged tissue, useful in helping to understand the results shown in FIGS. 12B-12D. The left side of the figure illustrates a cross section of an artery (all measurements in millimeters). ‘MED’ represents the thickness of the media layer of the arterial wall. ‘L’ represents the minimum distance of the thermally affected region from the lumen wall. ‘W’ represents the maximal width of the thermally effected region. ‘Th’ represents the thickness of the thermally affected region. ‘S’ represents the severity of the thermally affected region (e.g., as defined by a trained professional), defined as: 0=no thermal damage, 0.5=thermal damage to nerves only, 1=thermal damage to connective tissue in surrounding artery, 2=thermal damage to media (represents possible future risk of arterial stenosis).

Equations associating the parameters of ultrasound energy (frequency and intensity) to the thermal effect in tissue were developed by fitting the thermal damage parameters based on the histological analysis. Exemplary graphs are shown in FIGS. 13C-13H. Exemplary fitting coefficients (e.g., for duration of 30 seconds) are shown in the table below. Although coefficients correspond to a duration of 30 seconds, this is not intended to be limiting, and a similar analysis can be conducted for any other data points. It is emphasized that the coefficients in the table cannot be compared with each other. Each coefficient is distinct with reference to each formula. For example, the coefficient ‘b₁’ in formula 2 is different than the coefficient ‘b₁’ in formulas 3-7.

One possible function that associates the radial distance ‘L’ to the ultrasound treatment parameters of intensity (watt/cm²) and frequency (Mhz) is shown as:

$\begin{matrix} {{L\left( {I,f} \right)} = \frac{c_{1} - {c_{2}{\log \left( {c_{3}I} \right)}}}{{c_{4}f} + c_{5}}} & {{equation}\mspace{14mu} (1)} \end{matrix}$

Equation 1 contains 5 unknowns, but can be simplified to only 3 independent values, such as shown in equation 2. Some relationships represented by equation 2 are graphically illustrated by FIG. 13C.

$\begin{matrix} {{L\left( {I,f} \right)} = {\frac{b_{1} - {\log (I)}}{{b_{2}f} + b_{3}}.}} & {{equation}\mspace{14mu} (2)} \end{matrix}$

The relatively stronger flow of blood related to the relatively smaller diameter catheter in this group of experiments (2 mm vs 3 mm) is taken into consideration automatically by the proper choice of the first parameter in equation (2).

One possible function that associates the width ‘W’ to intensity and frequency is represented by equation 3. Some relationships represented by equation 3 are graphically illustrated by FIG. 13D.

W(I,f)=(b ₁ +b ₂ f)I+(b ₃ +b ₄ f)I ²  equation (3)

One possible function that associates the severity of the thermal effect ‘S’ to intensity and frequency is represented by equation 4. Some relationships represented by equation 4 are graphically illustrated by FIG. 13F.

W(I,f)=(b ₁ +b ₂ f)I+(b ₃ +b ₄ f)I ²  equation (4)

Some possible functions that associate the standard deviations of ‘L’, ‘W’ and ‘S’ to intensity and frequency include respective equations 5-7. Some relationships represented by equations 5-7 are graphically illustrated by respective FIGS. 13F-H.

$\begin{matrix} {{\sigma_{L}\left( {I,f} \right)} = {\frac{b_{1} + {b_{2}I}}{{b_{3}f} + b_{4}}.}} & {{equation}\mspace{14mu} (5)} \\ {{\sigma_{W}\left( {I,f} \right)} = {\frac{b_{1} + {b_{2}I}}{{b_{3}f} + b_{4}}.}} & {{equation}\mspace{14mu} (6)} \\ {{\sigma_{S}\left( {I,f} \right)} = {\frac{b_{1} + {b_{2}I^{2}}}{{b_{3}f} + b_{4}}.}} & {{equation}\mspace{14mu} (7)} \end{matrix}$

Parameter Formula b₁ b₂ b₃ b₄ L (2) 6.22 0.080 0.665 — W (3) 0.1374 −0.0044 −0.0065 0.00056 S (4) −0.0082 0.0039 0.00014 −1.9 · 10^(b) L (5) −0.069 0.012 −0.016 0.40 W (6) −1.87 0.45 −0.29 10.13 S (7) 1.66 0.0070 −0.53 18.18

Table of Exemplary Coefficients Corresponding to Exemplary Equations 2-7

The equations (parts A and B) illustrate that the frequency can be adjusted to control the area of thermal effect. For example, a relative increase in frequency can result in one or more of: the thermal effect being relatively closer to the wall edge, the width of the thermal effect being relatively increased, the severity of the thermal damage being relatively increased. The relative decrease in frequency can result in one or more of: the thermal effect being relatively further to the wall, the width is relatively reduced, the severity of the thermal damage is relatively reduced.

The equations further illustrate that the intensity can be adjusted to control the area of thermal effect. For example, a relatively increase in intensity can result in one or more of: the thermal effect being relatively further closer to the wall edge, the width of the thermal damage being relatively increased, the severity of the thermal damage being relatively increased. The relative decrease in intensity can result in one or more of: the thermal effect being relatively further from the wall, the width is relatively reduced, the severity of the thermal damage is relatively reduced.

As can be seen, various application times can be used as well.

In an exemplary embodiment of the invention equations can be used to calibrate the system. For example, the system can use the equations to provide an initial set of parameters. Optionally, treatment is synchronized to adjustments. For example, a thermal effect can be applied to a test region, or a small part of the target region. Feedback such as imaging can be performed to estimate the distance from the treated region to the arterial wall, the width of the region and/or the severity of the thermal effect (e.g., as described in co-filed PCT application with attorney docket number 52342). The actual measured values can be compared to the expected values. One or more parameters such as frequency and/or intensity can be adjusted relatively higher or relatively lower. The process can be repeated in a feedback-loop, thereby achieving the desired thermal effect to the desired area of tissue at the desired location.

Experimental Results

FIG. 12A is a table summarizing experimental results of selective thermal effects (e.g., damage) to arterial wall tissues, performed by the inventors, in accordance with some embodiments of the invention.

Experiments were performed in a total of 10 pigs, with multiple locations treated in the carotid and renal arteries. The pigs were under general anesthesia. The frequencies of ultrasound used were 10 Mhz, 15 Mhz and 20 Mhz. The intensity of acoustic ultrasound applied to the target tissue ranged from 1-10 watts/square centimeter to over 71 watts/square centimeter. The treatment duration was 30 seconds per location. The ultrasonic catheter used had a transducer with dimensions of 1.5 mm×6 mm×0.8 mm. The size of the catheter was 9 French. The length of the catheter was 55 cm when inserted into the renal artery, and a catheter having a length of 95 cm was used for the carotid artery.

In the set of experiments performed, the acoustic intensity was applied for about 30 seconds.

In the set of experiments performed, the thermal damaged initiated in the peri-adventitia, increasing towards the intima. The tables illustrate that the area of damage from the peri-adventitia inwards, for example, PA=damage localized to the peri-adventitia, M=damage from the peri-adventitia to the media, IEM=damage from the peri-adventitia to the internal elastic media. The area damaged (e.g., on a cross sectional histological slide through the artery) was summarized as S=small, M=medium and L=large. The definition of the damage (S, M, L), reflects the percentage of tissue with thermal effect in the relative sector with the pathology; S=1-20% thermal effect, M=21-60% thermal effect, L=>61% of thermal effect. The thermal effect was localized by sectors in a clockwise manner. The percentage effect represents the proportion of the thermal effect inside the defined sector. For example, “S” represents a string-like thermal zone, while “L” represents that most or all of the sector area was affected.

In the experiments performed, nerves in the peri-adventitia were thermally damaged, for example, Y=thermally damaged nerve, N=no thermally damaged nerves. The extent of thermal damage and/or the identification of thermally damaged nerves was conducted by a trained pathologist. In the experiments performed, the location of thermal damage in the arterial wall was selective. “Points” refers to the location (e.g., center of a treatment region) in the arterial wall by using an arbitrary clock as measurement, for example, 12 o'clock=0 degrees, 6 o'clock=180 degrees. The transducer was directed towards the affected sector.

In the experiments performed, multiple lesions were selectively made in a single blood vessel in a pig.

Experiment in the Aorta #1

Study subject: a female domestic pig, 71.7 Kg had been treated with an ultrasonic treatment system on its renal left artery. Anatomical target: nerves in the surrounding of the ostium of the right renal artery. Anatomical position of catheter: aorta artery, proximity to the ostium of right renal artery. Length of ultrasonic treatment catheter: 55 cm Transducer frequency: 20 MHz Time component of intensity profile: 30 seconds Acoustic intensity component of intensity profile: 52 Watts/cm̂2 Results: mild thermal effect was demonstrated at the peri adventitia.

-   -   FIG. 14A represents a 2× magnification of the location at the         aorta artery circumference that was treated with the ultrasonic         system, 6.0 mm proximal from the renal right ostium artery. The         marked area represents the border of the thermal effect seen in         the priadventitia, which manifests in an irreversible tissue,         and vessels necrosis, (T=Thermal).     -   FIG. 14B represents a 4× magnification of the thermal area.

Schematic Description of Pathology Analysis:

FIG. 14C represents a top view of all the artery layers (see index box as follows), at the relevant depth (6.0 mm from the renal right ostium). The artery is planned clockwise for the pathology definition.

The thermal effect seen in the artery is represented by the black area in the peri-adventitia, at sector 9.

Experiment in the Aorta #2

Study subject: a female domestic pig, 71.7 Kg had been treated with an ultrasonic treatment system on its renal left artery. Anatomical target: nerves in the surrounding of the ostium of the right renal artery. Anatomical position of catheter: aorta artery, proximity to the ostium of right renal artery. Length of ultrasonic treatment catheter: 55 cm Transducer frequency: 20 MHz Time component of intensity profile: 30 seconds Acoustic intensity component of intensity profile: 67 Watts/cm̂2 Results: nerves at the ostium of the aorta were treated.

-   -   FIG. 15A represents a 2× magnification of the location at the         aorta artery circumference that was treated with the ultrasonic         system, 6.5 mm proximal from the renal right ostium artery. The         marked area represents the border of the thermal effect seen in         the priadventitia, which manifests in an irreversible tissue,         and vessels necrosis, (T=Thermal). Furthermore the nerve which         was affected by the ultrasonic treatment is marked with XN,         which represents unviable nerves, expressed by necrosis of the         nerve.     -   FIG. 15B represents a 4× magnification of the thermal area and         the localization of the thermal necrotic nerve.     -   FIG. 15C represents a 10× magnification of the necrotic nerve         surrounded by tissue with thermal effect.

Schematic Description of Pathology Analysis:

FIG. 15D represents top view of all the artery layers (see index box as follows), at the relevant depth (6.5 mm from the renal right ostium). The artery is planned clockwise for the pathology definition.

The thermal effect seen in the artery is represented by the black area in the peri-adventitia, at sector 9.

Experiment in the Carotid Artery #1

Study subject: a female domestic pig, 72.8 Kg had been treated with an ultrasonic treatment system on its carotid left artery. Anatomical target: nerves in the wall of the right common carotid artery. Anatomical position of catheter: Right common carotid artery. Length of ultrasonic treatment catheter: 95 cm Transducer frequency: 20 MHz Time component of intensity profile: 30 seconds Acoustic intensity component of intensity profile: 34 Watts/cm̂2 Results: thermal effect was demonstrated from the media layer throughout the priadventitia of the right common carotid artery.

-   -   FIG. 16A represents a 2× magnification of the location of the         thermal effect at the circumference of the right common carotid         artery. The marked area represents the border of the thermal         effect seen in the media throughout the priadventitia layer,         which manifests in pyknosis of the smooth muscle cells and focal         collagen condensation.     -   FIG. 16B represents a 4× magnification of the thermal area

Schematic Description of Pathology Analysis:

FIG. 16C represents top view of all the artery layers (see index box as follows), at the relevant depth. The artery is planned clockwise for the pathology definition.

The thermal effect seen in the artery is represented by the black area in the peri-adventitia, at sector 1-3.

Experiment in the Carotid Artery #2

Study subject: a female domestic pig, 78.0 Kg had been treated with an ultrasonic treatment system on its carotid left artery. Anatomical target: nerves in the wall of the left common carotid artery. Anatomical position of catheter: left common carotid artery. Length of ultrasonic treatment catheter: 95 cm Transducer frequency: 20 MHz Time component of intensity profile: 30 seconds Acoustic intensity component of intensity profile: 13.2 Watts/cm̂2 Results: nerves surrounding the left common carotid artery were treated

-   -   FIG. 17A represents a digital scan of the 28.5 mm from the aorta         arch slide. The thermal effect is manifested in an irreversible         tissue, and vessels necrosis in less than 25% of the peri         adventitia in the artery circumference. Furthermore nerves which         were affected by the ultrasonic treatment are found to be         necrotic.

Schematic Description of Pathology Analysis:

FIG. 17B represents top view of all the artery layers (see index box as follows), at the relevant depth (6.5 mm depth from the aorta). The artery is planned clockwise for the pathology definition.

The thermal effect seen in the artery is represented by the black area in the peri-adventitia, at sector 3.

Experiment in the Renal Artery #1

Study subject: a female domestic pig, 68.2 Kg had been treated with an ultrasonic treatment system on its renal left artery. Anatomical target: nerves in the wall of the left renal artery. Anatomical position of catheter: left renal artery. Length of ultrasonic treatment catheter: 55 cm Transducer frequency: 10 Mhz Time component of intensity profile: 30 seconds Acoustic intensity component of intensity profile: 26 Watts/cm̂2 Results: nerves surrounding the left renal artery were treated

-   -   FIG. 18A represents a 2× magnification of the 6.5 mm depth from         the aorta slide. The marked area represents the border of the         thermal effect seen in the priadventitia, which manifests in an         irreversible tissue, and vessels necrosis, (T=Thermal).         Furthermore the nerves which were affected by the ultrasonic         treatment are marked with XN, which represents unviable nerves.         Both nerves in the surrounding of thermal area are necrotic.     -   FIG. 18B represents a 4× magnification of the thermal area, and         the localization of the thermal necrotic nerves.     -   FIG. 18C represents a 10× magnification of the necrotic nerves         inside the thermal effect zone.     -   FIG. 18D represents a 10× magnification of the necrotic nerve         outside the thermal effect zone. Both nerves' necrosis caused by         the thermal ultrasonic treatment.     -   FIG. 18E represents a 2× magnification of the 6.5 mm depth from         the aorta slide stained in PSR, before applying the polarizer         lens.     -   FIG. 18G represent a 2× magnification of the 6.5 mm depth from         the aorta slide, examined under polarizer light, representing a         distinctive negative birefringence caused by collagen         denaturation as consequence of the ultrasonic treatment. The         marked area represents the border of the thermal effect seen in         the priadventitia.

Schematic Description of Pathology Analysis:

FIG. 18G represents top view of all the artery layers (see index box as follows), at the relevant depth (6.5 mm depth from the aorta). The artery is planned clockwise for the pathology definition.

The thermal effect seen in the artery is represented by the black area in the peri-adventitia, at sector 5.

Pathology Analysis: Pathology Report Prepared by a Trained Pathologist

The table below represents the pathology report for the experiment. The table contains columns with the artery layers, different potential pathologies relevant to the artery layer, slide ID with a categorical scoring of lesions (as detailed below), and a sector (S) column for the localization of the pathology damage in clockwise manner.

Slide ID: N05-R- PIG No. N05-R-L3 L3 + 0.5 Sector Status Lumen Free thrombus 0 Endothelium Pyknosis 0 Endothelium Attached thrombus 0 Endothelium Fibrin deposition 0 Endothelium Erosion 4  1-12 Int. Elastic Distorted 0 Lamina Int. Elastic Rupture 1 11-1 Lamina Media Inflammation 0 Media Pyknosis* 1 11-1 Media Necrosis 0 Media Damage width (%) 40-  11-1 Vasa-Vasorum Thrombus 0 Vasa-Vasorum Fibrin 0 Vasa-Vasorum Necrosis 0 Adventitia Pyknosis 0 Adventitia Necrosis 0 Adventitia Inflammation 0 P. Adventitia Necrosis 1 5 THERMAL vessels P. Adventitia Thrombus 0 vessels Peri Adventitia Inflammation 0 Peri Adventitia Necrosis 1 5 P. Adventitia Degeneration/ 0 nerves vacuolation P. Adventitia Inflammation 0 nerves P. Adventitia Necrosis 1 5 nerves

For lesion scoring: 0: Normal Media damage width (%, maximum width given): 1: Minimal or X−: damage from the lumen towards the involving 0-25% periphery of the vessel of the vessel circumference 2: Mild or X+: damage from the periphery towards involving 25-50% the lumen of the vessel of the vessel circumference 3: Moderate or A: Artifact on histological processing involving 50-75% of the vessel circumference 4: Marked/Severe or S-Clockwise sector involving 75-100% of the vessel circumference

Experiment in the Renal Artery #2

Study subject: a female domestic pig, 65.7 Kg had been treated with an ultrasonic treatment system on its renal left artery. Anatomical target: nerves in the wall of the right renal artery. Anatomical position of catheter: right renal artery. Length of ultrasonic treatment catheter: 55 cm Transducer frequency: 20 Mhz Time component of intensity profile: three times for a period of 30 second each Acoustic intensity component of intensity profile: 53 Watts/cm̂2, 59 Watts/cm̂2 and 66 Watts/cm̂2 respectively. Results: thermal effect was demonstrated at the peri adventitia of the right renal artery.

-   -   FIG. 19A represent a 2× magnification of the 6.5 mm depth from         the aorta slide. The marked area represents the border of the         thermal effect seen in the priadventitia, which manifests in an         irreversible tissue necrosis, (T=Thermal).     -   FIG. 19B represents a 4× magnification of the thermal area. No         nerves were affected at this treatment.

Schematic Description of Pathology Analysis:

FIG. 19C represents top view of all the artery layers (see index box as follows), at the relevant depth (6.5 mm depth from the aorta). The artery is planned clockwise for the pathology definition.

The thermal effect seen in the artery is represented by the black area in the peri-adventitia, at sector 6-7.

Pathology Analysis: Pathology Report Prepared by a Trained Pathologist

The table below represents the pathology report for the experiment. The table contains columns with the artery layers, different potential pathologies relevant to the artery layer, slide ID with a categorical scoring of lesions (as detailed below), and a sector (S) column for the localization of the pathology damage in clockwise manner.

Slide ID: PIG No. N06-R-R4 N06-R-R4 + 0.5 Sector Lumen Free thrombus 0 Endothelium Pyknosis 0 Endothelium Attached thrombus 0 Endothelium Fibrin deposition 1 12 Endothelium Erosion 2 9-3 Int. Elastic Lamina Distorted 0 Int. Elastic Lamina Ruptured 1 12 Media Inflammation 0 Media Pyknosis* 1 12 Media Necrosis 0 Media Damage width (%) <10-   12 Vasa-Vasorum Thrombus 0 Vasa-Vasorum Fibrin 0 Vasa-Vasorum Necrosis 0 Adventitia Pyknosis 0 Adventitia Necrosis 0 Adventitia Inflammation 0 P. Adventitia vessels Necrosis 0 P. Adventitia vessels Thrombus 0 Peri Adventitia Inflammation 0 Peri Adventitia Necrosis 1 6-7 P. Adventitia nerves Degeneration/ 0 vacuolation P. Adventitia nerves Inflammation 0 P. Adventitia nerves Necrosis 0

For lesion scoring: 0: Normal Media damage width (%. maximum width given): 1: Minimal or X−: damage from the lumen towards the involving 0-25% periphery of the vessel of the vessel circumference 2: Mild or X+: damage from the periphery towards the involving 25-50% lumen of the vessel of the vessel circumference 3: Moderate or A: Artifact on histological processing involving 50-75% of the vessel circumference 4: Marked/Severe or involving 75-100% of the vessel circumference

Experiment in the Renal Artery #3

Study subject: a female domestic pig, 65.7 Kg had been treated with an ultrasonic treatment system on its renal left artery. Anatomical target: nerves in the wall of the right renal artery. Anatomical position of catheter: right renal artery. Length of ultrasonic treatment catheter: 55 cm Transducer frequency: 20 MHz Time component of intensity profile: twice for a period of 30 second each Acoustic intensity component of intensity profile: 40 Watts/cm̂2 and 53 Watts/cm̂2 Results: nerves surrounding the right renal artery were treated

-   -   FIG. 20A represents a 2× magnification of the 10.5 mm depth from         the aorta slide. The marked area represents the border of the         thermal effect seen in the priadventitia, which manifests in an         irreversible tissue, and vessels necrosis, (T=Thermal).         Furthermore the nerves which were affected by the ultrasonic         treatment are marked with XN, which represents unviable nerves,         and VN, which represent viable nerves. In the surrounding of         thermal area are present 8 nerves, including 7 unviable.     -   FIG. 20B represents a 4× magnification of the thermal area.     -   FIGS. 20C-E represents a 10× magnification of the necrotic         and/or vacuolated nerves inside the thermal effect zone.     -   FIGS. 20E-I represents a 10× magnification of the necrotic         and/or vacuolated and viable nerves outside the thermal effect         zone.

Schematic Description of Pathology Analysis:

FIG. 20J represents top view of all the artery layers (see index box as follows), at the relevant depth (10.5 mm depth from the aorta). The artery is planned clockwise for the pathology definition.

The thermal effect seen in the artery is represented by the black area in the peri-adventitia, at sector 4-5.

Renal Denervation Study Goal:

Inventors performed a controlled study to evaluate the clinical feasibility and/or safety of performing a renal denervation procedure in a chronic swine model, in accordance with some embodiments of the invention.

Study End Points

-   -   Primary: A significant decrease in norepinephrine levels at 30         days following the procedure, in the treatment group compared to         the control group.     -   Secondary: Lack of procedure related stenosis in the treated         renal arteries at 30 days following the procedure.

Experimental Materials

-   -   Equipment: An ultrasound emission element, catheter and control         system as described herein and/or in the related applications         was used to perform the treatments. A 10 Mhz ultrasound emission         element was used in the first set of experiments. A 20 Mhz         element was used in the second set of experiments.     -   Animals and preparation: All aspects of the study were approved         by the Animal Research Committee. A total of 10 Yorkshire         domestic swine (weight 70-75 Kg) were used for the first set of         experiments, 4 underwent the renal denervation procedure and 6         served as control. 5 additional pigs were used for the second         set of experiments, all underwent the procedure.     -   Animal preparation: Anatomic eligibility was confirmed by         angiography prior to the treatment. No animals were         disqualified. The experiment was performed under general         anesthesia. Intravenous heparin was administered to achieve an         intraprocedural activated clotting time (ACT)>250 seconds. At         the end of the procedure the animals were euthanized.

Experimental Protocol Ultrasonic Treatment:

In the experimental swine group, the catheter was advanced via a femoral approach to access the renal arteries. Ultrasound treatment, in accordance with some embodiments of the invention, was administered at the main arterial trunks in one or more locations. In each location, the ultrasound energy was directed in up to 4 angles of the arterial circumference (e.g., 0°, 90°, 180°, 270°—equivalent to 12, 3, 6, 9 hours in a clock model). Ablation of neural tissue was performed by ultrasonic excitation of 10 or 30 seconds in each treatment location. In actual practice, a smaller or larger number of angle may be used.

The catheter distance from the artery wall was measured using ultrasonic imaging of the system, prior to ultrasonic excitation, in accordance with some embodiments of the invention. If needed, a distancing device (e.g., as described with reference to co-filed PCT application “Separation device for ultrasound transducer”, attorney docket number 52348) was deployed, such as a part of the safety mechanism.

Control:

No ultrasonic energy was applied to the 6 swines in the control group. One control animal was cannulated and the catheter was introduced to the renal arteries without ultrasonic energy delivery.

Angiography:

Angiography was performed during three time periods; prior to the procedure, immediately at the end of procedure, and at 30 days+2 days. Under angiography, each renal artery was examined by a trained physician for stenosis, constriction and/or any abnormalities in blood flow.

Biopsy:

All experimental and control animals were biopsied. In vivo, open bilateral renal cortex biopsies were conducted in order to perform a norepinephrine (NE) quantitative analysis. The biopsy was taken from the cranial and caudal poles of the kidney under direct vision. Samples were sent to analysis of NE levels in the tissue using HPLC.

Histology:

The renal arteries and kidneys were perfused, dissected and immersed in 4% formalin prior to histological processing. Pathological examination for any thermal or mechanical damage to the renal arteries and connective tissue, including nerves.

Procedure Parameters

Procedure parameters are described for the first set of experiments.

An average of about 6.5+0.5 ultrasonic treatments were performed in the right renal artery in two locations along the artery, and about 4.5+1.0 ultrasonic treatments were performed in the left artery, in 1-2 focal locations along the artery. In an exemplary embodiment of the invention, a number of treatments can be performed in a number of locations. For example, 1, 2, 4, 8 or other smaller, intermediate or larger treatment locations are available. For example, 1, 2, 4, 6, 8, 12 or other smaller, intermediate or larger numbers of treatments can be performed in an artery.

Ultrasonic ablations were applied in one of two time durations, 10 seconds or 30 seconds. In an exemplary embodiment of the invention, the treatment time is about 1 second, about 5, 10, 15, 20, 25, 30, 35, 50, 60, 100 seconds or other smaller, intermediate or larger time periods are used.

The average total procedure time was about 35.2+13.3 minutes. The maximal temperature measured by the sensor close to the ultrasonic transducer was about 44.25+1.0 degrees Celsius in the right renal artery, and about 45.2+3.4 degrees Celsius in the left renal artery. The temperatures are considered safe.

Table Summarizing the Treatment Parameters

Number of Number of Number of treated Number of treated excitations locations excitations locations in right in right in left in left Duration of Animal renal renal renal renal treatment ID artery artery artery artery (seconds) 7917 6 2 4 1 30 7918 7 2 6 2 30 7920 6 2 4 1 10 7921 7 2 4 1 10

Results

Norepinephrine (NE):

Renal tissue NE content was used as a chemical marker of the sympathetic nervous system activity. Denervation of the sympathetic nervous system potentially causes a reduction in NE release from the sympathetic nerves terminals, indicating reduced sympathetic activity.

The mean reduction in NE concentration (normalized and averaged over different parts of the kidney) in renal tissue in the treated animals in comparison to the control group was, on the average, greater than 50% after 30 days. Longer treatment durations generally caused a greater reduction.

Angiography:

Neither perfusion defects nor artery constriction were depicted in the treatment group of animals, neither at the treatment time point, nor at the 30 day follow up. Mild spasm had occurred coincidentally during the treatment, with no sign of permanent spasm or abnormalities remaining or forming de-novo in the 30 days following treatment.

Histopathology:

There was no stenosis in any of the renal artery vessels in all levels. All vessels were potent in all levels.

CONCLUSION

As illustrated by the decrease in NE levels, all 10 pigs were successfully treated by renal denervation using ultrasound energy, in accordance with some embodiments of the invention. A relatively longer treatment (e.g., 30 seconds vs. 10 seconds) resulted in a relatively larger decrease of NE levels, suggesting that longer treatment times disrupt a larger number of nerves and/or nerves to a greater degree. Furthermore, some embodiments as described herein have been shown to be safe, as no abnormalities occurred to the renal arties during and immediately post treatment, as well as at 30 days.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

GENERAL

It is expected that during the life of a patent maturing from this application many relevant ultrasound transducers will be developed and the scope of the term transducer is intended to include all such new technologies a priori.

As used herein the term “about” refers to ±10%

The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion. 

1. A method of setting up a treatment system for non-focused ultrasound energy delivered intrabody comprising: selectively determining a target tissue in a wall of a lumen or cavity; selecting parameters sufficient to provide a desired therapeutic effect in said target tissue and which start a thermal damage effect only at a distance of at least 0.2 mm from an inner side of said wall; and setting up a treatment system using said parameters.
 2. A method according to claim 1, further comprising deciding an amount of desired thermal damage.
 3. A method according to claim 2, wherein said amount of thermal damage comprises a volume where thermal damage is desired.
 4. A method according to claim 2, wherein said amount of thermal damage comprises the degree of thermal damage.
 5. A method according to claim 1, further comprising selecting an anatomical location from which to treat said target tissue.
 6. A method according to claim 5, wherein said anatomical location comprises a renal artery and said target tissue comprises renal artery nerves.
 7. A method according to claim 5, wherein said anatomical location comprises an aorta and said target tissue comprises renal nerves.
 8. A method according to claim 5, wherein said anatomical location comprises a carotid artery and said target tissue comprises nerves.
 9. A method according to claim 1, wherein selecting comprises taking blood cooling into account.
 10. A method according to claim 1, wherein selecting comprises selecting in a manner which avoids significant stenosis.
 11. A method according to claim 1, wherein selecting comprises selecting in a manner which avoids significant damage to non-target tissue.
 12. A method according to claim 1, wherein selecting comprises selecting in a manner which avoids significant shrinkage in target tissue.
 13. A method according to claim 1, wherein said desired effect comprises denaturing at least some of said target tissue.
 14. A method according to claim 13, further comprising applying said ultrasound energy so as to not denature at least some part of said target tissue.
 15. A method according to claim 1, wherein said target tissue and said parameters are preselected so that said parameters have said desired effect on said target.
 16. A method according to claim 1, wherein said selecting comprises determining according to an attenuation coefficient of tissues.
 17. A method according to claim 1, further comprising selecting a margin of safety.
 18. A method according to claim 17, wherein said selecting a margin of safety comprises selecting an allowed amount of thermal damage to tissues surrounding said target tissue.
 19. A method according to claim 17, wherein said selecting a margin of safety comprises reducing or preventing contraction of said lumen or said cavity.
 20. A method according to claim 1, wherein said selectively determining said target tissue comprises selecting a type of tissue.
 21. A method according to claim 20, wherein said type of tissue comprises nerve tissue.
 22. A method according to claim 20, wherein said target tissue is selected from tissue located at a tissue layer selected from the group comprising peri-adventitia, adventitia, media, intima.
 23. A method according to claim 1, wherein said target tissue is located less than 10 mm from a renal ostium.
 24. A method according to claim 1, wherein said determining initial parameters comprises determining according to a distance of said target tissue from an intima.
 25. A method according to claim 24, wherein said target tissue is outside said wall of said lumen or said cavity.
 26. A method according to claim 1, further comprising selecting a frequency of treatment in the range of 8-25 Mhz.
 27. A method according to claim 1, further comprising selecting an ultrasound intensity in the range of 1-100 Watt/square centimeter.
 28. A method according to claim 1, wherein said target tissue is a renal nerve, and said parameters are an applied frequency of 10[MHz]-22[MHz], and an intensity of 10-40[W/cm̂2].
 29. A method according to claim 1, wherein a duration of said treatment is 5-30 seconds.
 30. A method according to claim 1, wherein a length of said lumen or cavity is less than 20 mm.
 31. A method according to claim 1, comprising applying said parameters to selectively treat said target tissue using non-focused ultrasound to achieve said desired effect.
 32. A method according to claim 31, further comprising obtaining feedback associated with said treatment.
 33. A method according to claim 32, further comprising adjusting said parameters according to said feedback and retreating said target tissue.
 34. A method according to claim 31, further comprising a controlled adjustable treatment according to online measurements including at least one of the following group of measurements: flow measurements, current measurement, voltage measurement, power measurement, acoustic backscatter measurements, temperature measurements, pressure measurements.
 35. A method according to claim 31, wherein treating comprises applying said ultrasound away from said wall but inside a body.
 36. A method according to claim 31, applying so that a desired effect comprises temporary change in tissue functionality is achieved.
 37. A method according to claim 31, wherein said applying said parameters comprises applying said parameters in an open loop manner.
 38. A method according to claim 31, wherein applying comprises applying said ultrasound energy so as to not denature most of the tissue between said target tissue and an edge of said wall.
 39. A method according to claim 31, wherein applying comprises maintaining blood in said lumen at a temperature below 50 degrees Celsius.
 40. A method according to claim 31, wherein applying comprises maintaining blood in said lumen at a temperature below 43 degrees Celsius.
 41. A method according to claim 31, wherein said applying comprises heating a nerve while not heating tissue outside of a fat sheath surrounding said nerve.
 42. A method according to claim 31, wherein said applying comprises localizing heating by having a gradient of cooling from blood and a gradient of heating from a distance.
 43. A method according to claim 31, wherein applying comprises heating nerves sufficiently to reduce renal norepinephrine levels by at least 50%.
 44. A method according to claim 31, wherein applying comprises heating a part of a nerve to necrosis while not heating another part of said nerve in a same axial location along said nerve to necrosis.
 45. A method according to claim 31, further comprising adjusting a property of at least one of said target tissue, said wall and blood in said lumen to provide said desired effect.
 46. A method according to claim 45, wherein said property comprises a rate of heat removal.
 47. A method according to claim 45, wherein said property comprises a flow rate of said blood.
 48. A method according to claim 45, wherein said property comprises a temperature.
 49. A method according to claim 31, wherein said applying comprises applying said ultrasound energy so as to treat a patient suffering from hypertension.
 50. A method according to claim 31, wherein said applying comprises applying said ultrasound energy so as to prevent signals from propagating through at least one renal nerve.
 51. A method according to claim 31, wherein said applying comprises applying said ultrasound energy so as to position said treatment area with an accuracy of better than 0.2 mm along an axis perpendicular to said wall.
 52. A system for treating a blood vessel wall comprising: a catheter; at least one ultrasound emitter mounted on the catheter and adapted for emitting unfocused ultrasound at a frequency of 10-40 Mhz at a target tissue located a distance from an intima of the blood vessel wall with a power setting sufficient to heat said target tissue; and a controller, wherein the controller is configured to deliver enough power to heat said target tissue to a selected size and to a desired thermal effect, said thermal effect starting only after at least a distance of 0.2 mm from said wall.
 53. A system according to claim 52 wherein said target tissue comprises nerves, and said desired thermal effect comprises reducing signals through said nerves by at least 50%.
 54. A system according to claim 52, wherein said catheter is configured so that said emitter does not contact said wall.
 55. A system according to claim 52, wherein said controller is configured to selectively treat a volume of tissue distanced from an intima of a blood vessel wall.
 56. A system according to claim 52, wherein said controller is configured for thermal treatment of renal nerves.
 57. A system according to claim 52, wherein said controller is configured for treatment accuracy of better than 0.5 mm positioning of the treatment area, along a dimension perpendicular to said blood vessel.
 58. A system according to claim 52, wherein said controller is configured for treatment specificity which avoids significant vessel stenosis as an aftermath of said treatment.
 59. A system according to claim 52, wherein said controller is configured to selectively heat nerves within a fat sheath thereof.
 60. A system according to claim 52, wherein said controller is configured with a protocol including a plurality of treatment regions and sufficient to reduce hypertension if applied to renal nerves.
 61. A system according to claim 52, wherein said controller is pre-configured with sets of parameters matching different target tissues and target tissue locations.
 62. A system according to claim 52, wherein said controller includes a feedback circuit for real-time control of settings of said system.
 63. A method of setting up a device to selectively treating tissue using non-focused ultrasound energy delivered intrabody comprising: setting up said device to be suitable for heating a selected area of tissue at a selected location from an arterial wall. 64-67. (canceled)
 68. A method of setting up a device to selectively treating tissue using non-focused ultrasound energy delivered intrabody comprising: setting up said device to be suitable for heating nerve tissue while not heating, to a tissue damaging level, tissue outside a fat sheath surrounding said nerve.
 69. A method of reducing blood pressure comprising: applying unfocused ultrasonic energy to the renal ostium from within a blood vessel, said energy sufficient to disrupt signals propagating through renal nerves. 70-71. (canceled)
 72. A method for treating a patient experiencing a clinical disorder, the method comprising: positioning at least one unfocused ultrasound emitter at an anatomical location proximate to a target tissue; selectively delivering unfocused ultrasound energy to the target tissue; and selectively causing thermal damage to at least a portion of the target tissue, to provide a desired treatment, no significant thermal damage being caused closer than 0.2 mm to said wall.
 73. The method of claim 72 wherein the target tissue comprises body lumen, fat, nerves, vasa vasora, lymph, tumor, connective tissue, or plaque.
 74. The method of claim 72 wherein the anatomical location comprises a blood vessel or artery.
 75. The method of claim 74 wherein the anatomical location is the renal artery and the target tissue comprises one or more renal artery nerves.
 76. The method of claim 74 wherein the at least one unfocused ultrasound emitter is configured not to touch the wall of the blood vessel or artery.
 77. The method of claim 74 wherein the at least one unfocused ultrasound emitter is positioned as to not substantially block blood flow in the blood vessel or artery.
 78. The method of claim 77 wherein the at least one unfocused ultrasound emitter, in operation, is cooled by the blood flow.
 79. The method of claim 72 wherein the clinical disorder comprises at least one of sleep apnea, obesity, diabetes, end stage renal disease, lesion on a body lumen, contrast nephropathy, heart arrhythmia, congestive heart failure, and hypertension.
 80. The method of claim 74 further comprising determining the distance from the blood vessel or artery wall to the target tissue and selecting the frequency of the unfocused ultrasound energy based upon on said distance of the target tissue.
 81. The method of claim 72 wherein the frequency of the unfocused ultrasound energy is 10-22 Mhz.
 82. The method of claim 72 wherein the target tissue comprises a treatment region.
 83. The method of claim 82 further comprising determining the treatment region and selecting the intensity of the unfocused ultrasound energy according to the size of the treatment region.
 84. The method of claim 77 further comprising delivering the at least one unfocused ultrasound emitter intrabody within the blood vessel or artery by a delivery catheter and configuring the delivery catheter to prevent the at least one unfocused ultrasound emitter from touching the wall of the blood vessel or artery.
 85. The method of claim 72 further comprising selecting the target tissue using parameters obtained from an equation based upon empirical data.
 86. The method of claim 85 wherein the equation is: x(f,I) [mm]=(C6+a*Exp(flow*b)−C2*log(C3*I [W/cm̂2]))/(C4*f [MHz]+C5) Wherein, “I” is excitation intensity [W/cm̂2]; “f” is working excitation frequency [MHz]; “x” is minimal radial distance from the artery wall [mm]; and “flow” is blood flow rate in the artery [ml/mm].
 87. The method of claim 72 further comprising receiving feedback indicating the thermal damage to the target tissue.
 88. The method of claim 87 further comprising modifying the parameters in response to said feedback.
 89. The method of claim 72 further comprising selectively delivering the unfocused ultrasound energy in a manner such that there is no significant damage to non-target tissue.
 90. The method of claim 72 further comprising selectively delivering the unfocused ultrasound energy in a manner such that there is no significant stenosis.
 91. The method of claim 72 further comprising delivering unfocused ultrasound energy to at least one treatment region, each treatment region being at a separate circumferential location.
 92. The method of claim 91 wherein the duration that unfocused ultrasound energy is delivered to the target tissue is 5-30 seconds per treatment region.
 93. The method of claim 91 wherein the treatment comprises between 1 and 8 treatment regions. 